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Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-023447 review only Article Type: Research

Date Submitted by the Author: 09-Apr-2018

Complete List of Authors: Mubanga, Mwenya; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory Byberg, Liisa; Uppsala Universitet, Department of Surgical Sciences, Orthopedics, Uppsala University Egenvall, Agneta; Swedish University of Agricultural Science, Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary Epidemiology Sundström, Johan; Uppsala University Magnusson, Patrik; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Ingelsson, Erik; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory; Stanford University Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, http://bmjopen.bmj.com/ Fall, Tove; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory

Cardiac Epidemiology < CARDIOLOGY, EPIDEMIOLOGY, Hypertension < Keywords: CARDIOLOGY, General diabetes < DIABETES & ENDOCRINOLOGY

on September 29, 2021 by guest. Protected copyright.

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1 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Dog ownership and Cardiovascular Risk Factors: a nationwide prospective 4 5 register-based cohort study 6 7 Mwenya Mubanga, MBChB, MPH1; Liisa Byberg, PhD2; Agneta Egenvall, VMD, PhD3; 8 9 Johan Sundström MD, PhD4, Patrik K Magnusson, PhD5; Erik Ingelsson, MD, PhD1,6,7; Tove 10 11 1* 12 Fall, VMD, PhD 13 14 15 1. Department of Medical Sciences, Molecular Epidemiology and Science for Life 16 For peer review only 17 Laboratory, Uppsala University, Uppsala, Sweden. 18 19 2. Department of Surgical Sciences, Orthopedics, Uppsala University, Uppsala, Sweden. 20 21 3. Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary 22 23 Epidemiology, Swedish University of Agricultural Sciences, Uppsala, Sweden. 24 25 4. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 26 27 28 Uppsala. Sweden. 29 30 5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 31

32 Stockholm, Sweden. http://bmjopen.bmj.com/ 33 34 6. Department of Medicine, Division of Cardiovascular Medicine, Stanford University 35 36 School of Medicine, Stanford, CA, USA. 37 38 7. Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA. 39

40 on September 29, 2021 by guest. Protected copyright. 41 42 43 44 *Corresponding author: Tove Fall, VMD, PhD, [email protected] 45 46 47 Word count: 3090 words (max 4000) 48 49

50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 45

2 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Abstract (297 words; max 300) 4 5 Objective: To study the association between dog ownership and cardiovascular risk factors. 6 7 Design: A nationwide register–based prospective cohort study with a crosssectional study in 8 9 a subset of the population. Participants were followed up from October 1st, 2006 to December 10 31st, 2012. 11 12 13 Setting: A cohort of 2,026,865 participants was identified from the Register of the Total 14 Population and linked to other national registers for information on dog ownership, hospital 15 16 admissions, socioeconomicFor peer status and countryreview of birth. Participants only were followed up to 17 medication for a cardiovascular risk factor, emigration, death or at the end of the study on 18 19 December 31st, 2012. Crosssectional associations were further assessed in 10,110 individuals 20 21 from TwinGene. 22 st 23 Participants: All Swedish residents aged 4580 years on October 1 , 2006. 24 25 Main outcome measures: Initiation of treatment for hypertension, dyslipidemia and diabetes 26 mellitus. 27 28 29 Results 30 31 The results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95%

32 CI, 1.011.03) and lipidlowering treatment (HR, 1.02; 95% CI, 1.011.04) in dog owners than http://bmjopen.bmj.com/ 33 34 in nonowners, particularly amongst those aged 45 to 60 and in those owning mixed breed or 35 36 companion/toy breed dogs. No association of dog ownership with initiation of treatment for 37 diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.951.01). Sensitivity analyses 38 39 in the TwinGene cohort indicated confounding from factors not available in the national

40 cohort, such as employment status and nonCVD chronic disease status. on September 29, 2021 by guest. Protected copyright. 41 42 43 Conclusions 44 45 In this large cohort study, dog ownership was not associated with any large reduction in 46 initiation of medication for classical cardiovascular risk factors, implying that the previously 47 48 reported lower risk of cardiovascular mortality among dog owners in this cohort is not 49 explained by reduced hypertension and dyslipidemia. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 45 BMJ Open

3 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Strengths and limitations of this study 4 5 • This is the largest study to date to examine the impact of dog ownership on 6 cardiovascular risk factors 7 • The nationwide registerbased cohort study with a crosssectional investigation in a 8 9 twin registry with a vast array of lifestyle and clinical variables strengthens the results 10 • The main outcome measures were extracted from nationwide registers thus decreasing 11 the risk of recall and selection bias. 12 Misclassification of dog ownership, particularly in the twin register, may have led to 13 • 14 some loss of power. 15 • Some important confounding factors were not available in the national data 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Introduction 4 5 There is a growing interest in pet ownership as a possible intervention to enhance 6 1 2 7 cardiovascular health and wellbeing. We recently observed that being registered as a dog 8 owner was associated with a lower risk of cardiovascular and allcause mortality in the 9 10 general Swedish population (n=3,432,153).3 Any causal association of dog ownership with 11 12 lower cardiovascular mortality could potentially be mediated through increased physical 13 activity or through the psychological benefits of companionship, which could in turn reduce 14 15 other important cardiovascular risk factors such as blood pressure, adiposity, dyslipidemia, 16 and insulin resistance.For An alternativepeer explanation review could be confounding only by socioeconomic, 17 18 cultural, demographic or psychosocial factors. A large number of crosssectional and 19 20 longitudinal studies across different countries support the association of dog ownership with 21 physical activity;1 however, reports regarding the association of dog ownership with other 22 23 cardiovascular risk factors are less consistent.411 These inconsistences may be due to low 24 25 statistical power in small studies, use of restricted or homogenous populations, inability to 26 control for differences across breed of dogs, or simply an absence of effect. As dogs are 27 1214 28 reported to be more common in rural areas compared to urban areas, as well as in 29 households with children,15 16 it is also important to account for these differences. 30 31

32 The aim of this study was to assess the association of dog ownership with three major clinical http://bmjopen.bmj.com/ 33 risk factors for cardiovascular disease, specifically initiation of treatment of hypertension, 34 35 dyslipidemia and diabetes mellitus. We investigated this using data from national registers on 36 37 dog ownership and drug prescriptions. We further sought to explore the association with other 38 cardiovascular risk factors using crosssectional data from a subcohort extracted from the 39

40 Swedish Twin Registry containing detailed information from questionnaire data, physical on September 29, 2021 by guest. Protected copyright. 41 42 examinations and laboratory measurements. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 45 BMJ Open

5 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Methods 4 5 Design 6 7 8 The main analysis was based on a nationwide cohort study of Swedish residents aged 4580 9 followed from October 1st 2006, to December 31st 2012. We additionally used cross 10 11 sectional data of participants (aged 4780) in the TwinGene study, which is a substudy of the 12 Swedish Twin Registry (Supplementary Figure 1). 13 14 15 Study Population – National Cohort 16 For peer review only 17 All Swedish residents (n=3,412,946) aged 4580 on October 1st 2006, were identified through 18 19 the Register of the Total Population. We excluded 11,298 individuals with unverified, reused 20 identification numbers or missing education information, and 137,306 additional individuals 21 22 that had resided in Sweden for <15 years to ensure complete linkage to medical information 23 24 and sufficient information regarding dog ownership in Sweden. We also excluded 531,658 25 individuals with a history of any CVD (International Classification of Disease (ICD)9 codes 26 27 390459 and ICD10 I00I99) or with a history of coronary artery bypass grafts or 28 29 percutaneous coronary artery intervention medical procedure (Nordic surgical procedure 30 codes FNA, FNC and FNG) from in and outpatient data from the National Patient Register 31

32 before October 1st, 2006. Inpatient data was available from 1987 and outpatient data from http://bmjopen.bmj.com/ 33 34 2001. Further, using data from the Swedish Prescribed Drug Register, which covers all 35 Swedish dispensed pharmacy prescriptions since it was established on July 1st 2005, 36 37 individuals (n=705,819) were excluded if they had any recorded dispensed prescription of 38 antihypertensive drugs, lipidlowering drugs, or glucose lowering drugs from 15 months 39

40 prior to baseline (which was when this register was initiated). Antihypertensive drugs were on September 29, 2021 by guest. Protected copyright. 41 42 defined based on the Anatomical Therapeutic Chemical Classification System (ATC) as 43 codes: C02 (antihypertensive drugs), C03A, C03EA01 (thiazide diuretics), C07 (beta receptor 44 45 blockers, excluding sotalol [C07AA07]), C08C (selective calcium antagonists with mainly 46 47 vascular effects) and C09 (agents acting on the reninangiotensin system). Lipidlowering 48 drugs were defined as C10AA (statins), C10AB (fibrates), C10AC (bile acid sequestrants), 49 50 C10AX (other lipidmodifying agents) and C10B (lipidlowering drug combinations). 51 Glucoselowering drugs were defined as ATCcode A10A (insulin and analogues) and A10B 52 53 (glucoselowering drugs excluding insulin). 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 45

6 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Study population – TwinGene 4 5 The TwinGene study originally included 12,614 (of 22,391 invited) twins from the 6 7 “Screening Across the Lifespan Twin study” (SALT) and was conducted between April 2004 8 and December 2008 and included a visit to their local health center and blood sampling 9 10 (Supplementary Figure 2).17 The studybase “SALT” was a substudy of the Swedish Twin 11 12 Register in twins born before 1959 and who participated in a telephonebased questionnaire 13 substudy from March 1998 to March 200217 (Supplementary Table 1). 14 15 16 We performed a Forcrosssectional peer analysis reviewof the association of only dog ownership with 17 cardiovascular risk factors in the TwinGene cohort (n=12,105). We excluded 1,373 18 19 individuals for having a previous history of CVD recorded in the National Patient Register.18 20 21 We also excluded 622 individuals for having missing or incomplete data (Supplementary 22 Figure 1). 23 24 25 Exposure 26 27 Dogs in Sweden are required to have a unique identifier (ear tattoo or implanted identity chip) 28 29 and this is registered alongside their owner’s unique personal identity number at the Swedish 30 Board of Agriculture. All dogs sold as purebred are registered by the Swedish Kennel Club. 31 We defined the variable ‘dog ownership’ in the national cohort as registered dog ownership or 32 http://bmjopen.bmj.com/ 33 having a partner registered as a dog owner in either the Swedish Board of Agriculture and/or 34 35 the Swedish Kennel Club, in a timeupdated manner throughout the study period. The linkage 36 37 to each respective partner (defined as a married couple, registered samesex partnership or a 38 cohabiting couple with common children) was possible through annual extracts from the 39

40 Register of the Total Population. on September 29, 2021 by guest. Protected copyright. 41 42 In the TwinGene data, we did not have access to information on partners’ dog ownership and 43 44 only each person’s own dog registrations were used. Dog ownership was defined at the date 45 46 of inclusion in TwinGene. 47 48 If information on a dog’s death was missing, we assumed a maximum lifespan of ten years. 49 50 Where birth or registration dates were discrepant between the two registers, we randomly 51 selected one of the two. We used the Swedish Kennel Club’s definition of breed groups to 52 53 categorize the 331 breeds into ten breed groups (Supplementary Table 2). All nonpurebred 54 dogs and those of unknown breed were included in an additional mixed breed group. Where 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 45 BMJ Open

7 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 owners had dogs of different breeds, we defined the breed based on the dog registered first 4 and where owners had several dogs, we restricted ownership to three dogs. 5 6 7 Based on previous findings of owners to hunting dogs having a lower risk of cardiovascular 8 events, we additionally defined a group of hunting dogs consisting of Terriers, Pointing, Scent 9 10 Hounds and Retrievers for analysis. 11 12 Outcome 13 14 15 In the national cohort, time to first dispensed prescription of antihypertensive drugs, lipid 16 lowering drugs orFor glucoselowering peer drugs review after baseline was onlydefined from data extracted from 17 18 the drug register. Participants were censored at emigration, death or at the end of the study on 19 20 December 31st, 2012. In the analysis of time to antihypertensive medication, individuals 21 were additionally censored at a diagnosis of heart failure, unstable angina or acute myocardial 22 23 infarction in the National Patient Register as the same drugs could be administered for their 24 25 treatment. 26 27 Prevalent use of antihypertensive, lipidlowering or glucoselowering drugs was defined 28 29 from the clinical questionnaire data collected during the TwinGene study. Cardiovascular risk 30 factors measured and also used as outcomes in TwinGene included blood glucose, 31 glycosylated hemoglobin A1c (HbA1c), high sensitive Creactive protein (hsCRP), 32 http://bmjopen.bmj.com/ 33 triglycerides, high density lipoproteincholesterol (HDLC), low density lipoprotein 34 35 cholesterol (LDLC), waisthip ratio, body mass index (BMI), systolic and diastolic blood 36 37 pressure and mean arterial pressure (MAP) (Supplementary methods). Only fasting 38 measurements of glucose and triglycerides were used (9,873 [97%] of all participants were 39

40 fasting). hsCRP and triglycerides were transformed to the natural log scale before analysis to on September 29, 2021 by guest. Protected copyright. 41 42 approach normality. 43 44 Statistical analyses 45 46 All statistical analyses were conducted using Stata version MP14.1 (StataCorp). Using age as 47 48 a timescale, separate multivariable Cox proportional hazards models were applied to assess 49 50 the associations between dog ownership and time to initiation of antihypertensive, lipid 51 lowering and glucoselowering drugs, respectively. Directed acyclic graphs were used to 52 53 guide the choice of covariates (Supplementary Figure 3). A first crude model included age and 54 sex, and a second model additionally included the region of birth, area of residence, level of 55 56 education, marital status and income. A description of the covariates is provided in the 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 45

8 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Supplementary methods. The proportional hazards assumption was verified by plotting 4 Schoenfield residuals and loglog graphs. Results were reported as hazard ratios (HR) and 5 6 95% confidence intervals (CI). 7 8 We repeated the calculations using the breed group as exposure to examine possible breed 9 10 group effects and we applied Bonferroni correction (for 11 breed groups) to control for 11 12 multiple testing. Further analyses were stratified by age group, sex, and whether participants 13 lived alone or not. Individuals considered as “living alone” did not have any spouse, partner 14 15 with common children, or children living in the same household. 16 For peer review only 17 We conducted a sensitivity analysis where we excluded βblockers as first line anti 18 19 hypertensive treatment to estimate the effect of changing treatment guidelines over the study 20 21 period. In additional sensitivity analysis, in the lipidlowering medication analysis, we 22 assessed the effect of censoring participants at a diagnosis of heart failure, unstable angina or 23 24 acute myocardial infarction in the National Patient Register. 25 26 Logistic regression was applied in TwinGene for the association of dog ownership with 27 28 prevalent antihypertensive, lipidlowering and bloodglucose lowering medication and linear 29 regression for the association of dog ownership with continuous variables. In addition to 30 31 adjusting for age, sex, presence of children in the household, area of residence, population

32 http://bmjopen.bmj.com/ 33 density, marital status, latitude of residence and level of education, we added one covariate at 34 a time to investigate their individual importance: tobacco use, occupational level, employment 35 36 status, Charlson comorbidity index and disability. In all twin analyses, standard errors were 37 38 adjusted with the robust sandwich estimator for dependent observations. For blood pressure 39 and lipid levels, associations were further stratified by current medication.

40 on September 29, 2021 by guest. Protected copyright. 41 Ethical approval 42 43 The regional ethical review board in Stockholm, Sweden, approved the study (national study: 44 45 2012/111431/2, with amendment 2013168732; TwinGene: 2007/64431/2 and 2016/1392 46 31/1). 47 48 49 Patient involvement 50 51 No patients were involved in the development, design or analysis of this study. The review 52 53 board allowed the researchers to waive the requirement for obtaining informed consent in the 54 national study. Participants in TwinGene provided written informed consent. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 45 BMJ Open

9 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Results 4 5 National Cohort 6 7 The baseline characteristics of 2,026,865 Swedish residents are shown in Table 1. Dog 8 9 ownership was directly registered in 189,355 (9.3%) at any time during the followup period, 10 and this increased to 295,682 (14.6%) individuals when partners’ registration were included. 11 12 At baseline, the average age of dog owners was 50 years vs 53 years in nonowners. Dog 13 14 owners were more likely to be married than nonowners (78% vs 60%) and more likely to live 15 in lowdensity areas than nonowners (median: 49 vs 77 inhabitants per square kilometer). 16 For peer review only 17 Compared to nonowners, mixed pedigree dog owners (n=32,003) were less likely to be 18 19 married (59 %), were less likely to have a tertiary education (21%) and had fewer people in 20 the top quintile for income (12.2%). Owners of huntingtype breeds showed similar 21 22 characteristics to the overall dog owners. 23 24 Medication for cardiovascular risk factors 25 26 During 10,692,258 personyears of followup, dog ownership was associated with a 2% 27 28 higher risk of initiation of antihypertensive drug medication in both crude and multivariable 29 30 adjusted analyses (HR, 1.02; 95% CI, 1.011.03). During 11,508,349 personyears of follow 31 up, there was a 2% higher risk of initiating lipidlowering medication in the multivariable

32 http://bmjopen.bmj.com/ 33 adjusted models (HR, 1.02; 95% CI, 1.011.04). During 12,207,964 personyears of follow 34 up, there was a lower risk of initiating glucose lowering drugs in dog owners in minimally 35 36 adjusted models (HR, 0.91; 95% CI, 0.890.94), but on multivariable adjustment, the 37 38 association was attenuated and nonsignificant (HR, 0.98; 95% CI, 0.951.01) (Table 2). 39 Owners of “Companion/toy” breeds and of dogs of mixed pedigree were at higher risk of anti

40 on September 29, 2021 by guest. Protected copyright. 41 hypertensive and lipidlowering drug initiation compared to nondog owners (Table 3). 42 43 Owners of the Spitz/primitive breed types and the combined group of hunting breed types had 44 45 lower risks of initiating glucoselowering medication (HR, 0.83; 95% CI, 0.740.93 and HR, 46 0.92; 95% CI, 0.860.97 respectively) while owners of mixed pedigree dogs had higher risk of 47 48 getting glucoselowering medication (HR, 1.18; 95% CI, 1.091.27) (Supplementary Figure 49 50 4). 51 52 There was no difference in strength of association when we excluded βblockers as firstline 53 treatment for antihypertension (Supplementary Table 3) or when censoring was done in 54 55 those being investigated for lipidlowering treatment initiation was made for angina, 56 myocardial infarction or heart failure was conducted (Supplementary Table 4). 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 45

10 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 In agestratified analysis, there were some evidence of effect modification by age for both 4 antihypertensive and lipidlowering drugs where an increased risk was observed in those 5 6 aged below 50 years (HR, 1.04; 95% CI, 1.011.08 and HR, 1.10; 95% CI, 1.041.15, 7 8 respectively), with estimates gradually approaching one with increasing age (Figure 1). 9 Inverse associations of dog ownership with glucoselowering drugs was observed in the lower 10 11 age groups, in males and those not living alone (HR, 0.89; 95% CI, 0.790.99, HR, 0.95; 95% 12 CI, 0.920.99 and HR, 0.91; 95% CI, 0.860.97, respectively). 13 14 TwinGene 15 16 For peer review only 17 On crosssectional analysis of 10,110 individuals, 484 (5%) were registered as dog owners 18 (partners’ dogs not included) and their characteristics are described in Table 1 and 19 20 Supplementary Table 5. Using similar covariates as in the national cohort, no associations of 21 22 dog ownership was found with prevalent use of antihypertensive drugs (OR, 0.94; 95% CI, 23 0.741.20), lipidlowering drugs (OR, 0.92; 95% CI, 0.651.29) or glucoselowering drugs 24 25 (OR, 0.90; 95% CI, 0.501.63) (Table 2). Upon inclusion of additional covariates, the 26 Charlson comorbidity score and the employment status were found to be the most influential 27 28 confounders and the fully adjusted model yielded lower but still nonsignificant estimates: 29 30 OR, 0.90 (95% CI, 0.701.15) for use of antihypertensive drugs, OR, 0.87 (95% CI, 0.62 31 1.22) for lipidlowering drugs or and OR, 0.78 (95% CI, 0.431.43) for glucoselowering

32 http://bmjopen.bmj.com/ 33 drugs (Supplementary Table 6). We found no association between dog ownership and the 34 other clinical and biochemical cardiovascular risk factors (Figure 2). 35 36 37 Discussion 38 39 In this nationwide study in a population without previous cardiovascular disease, we observed

40 on September 29, 2021 by guest. Protected copyright. 41 a minimally higher risk of initiation of treatment for hypertension and dyslipidemia among 42 persons with a dog in their household compared to those without dogs in the household. 43 44 Associations were most prominent in younger age groups (4060 years). Owning a dog of 45 mixed pedigree or a dog belonging to the “companion/toy” breed group was associated with 46 47 hypertension and dyslipidemia, whilst ownership of a dog from the “Spitz/primitive” breed 48 49 and the combined group of huntingtype breeds (Terriers, Pointing, Scent Hounds and 50 Retrievers) was associated with lower risk of treatment for diabetes mellitus. Crosssectional 51 52 analyses in 10,110 participants from TwinGene showed no association of dog ownership with 53 54 body mass index, waisttohipratio, blood pressure or biochemical cardiovascular risk 55 factors, and indicated that the association of dog ownership with medication for hypertension, 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 45 BMJ Open

11 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 dyslipidemia and diabetes was confounded by employment status and nonCVDchronic 4 conditions. 5 6 7 That owners of mixedbreed and “companion/toy” breeds, as well as dog owners in younger 8 age groups, had mildly increased risks for hypertension and dyslipidemia are in line with our 9 10 previous study regarding higher risk of myocardial infarction and stroke in this group. We 11 12 note that the proportion of highest education level in the mixed breed group was remarkably 13 lower than the general population (20.9% vs 29.3%). Although we adjusted for educational 14 15 level, it is likely that there is unmeasured confounding from differences in healthseeking 16 behavior, smokingFor habits orpeer stress in dogowners review in working onlyage groups. In TwinGene, we 17 18 noted that additional adjustment for employment status (unemployed, retired, sick leave or 19 20 unemployed) and a comorbidity index (for diseases other than CVD) were important 21 confounders lowering the estimates. These covariates were not available in the national 22 23 cohort, implying that the results in the national cohort are likely to have been confounded by 24 25 these or other factors. 26 27 Our findings in TwinGene are different from an Australian cohort study in 5,741 individuals 28 29 with 13.6% pet ownership who found lower levels of plasma cholesterol, triglycerides and 30 systolic blood pressures in petowners than nonowners.11 Dog owners (6.3%) had better self 31

32 rated health but no difference in blood pressure than nonpet owners in crosssectional http://bmjopen.bmj.com/ 33 analysis of the NordTrondelag Health Study (HUNT)3 study (n=12,297).4 34 35 36 There are a limited number of studies of the association between dog ownership and the risk 37 38 of type 2 diabetes. A study by Lentino et al., (n=916) showed that regular dog walkers 39 (n=399, 44%) in a primarily welleducated Caucasian population had lower BMI and were at

40 on September 29, 2021 by guest. Protected copyright. 7 41 lower risk of both dyslipidemia and type 2 diabetes than other study participants. These 42 findings were contradicted by Wright et al, who showed that dog owners were more likely to 43 44 be overweight, and have diabetes than nonowners in a study of 1179 community dwellers 45 10 46 with 30% pet ownership. Differences in findings across countries could be due to 47 differences in study design, or to inherent differences in dog management and the type of dog 48 49 breeds in the country. The level of dog walking might be lower in the smaller companion/toy 50 dogs breeds as compared to the huntingtype breeds.19 In TwinGene, 68% of hunting breed 51 52 owners reporting a high level of physical activity versus 52% in nondog owners. 53 54 55 Strengths and weaknesses 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 45

12 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 The main strengths of our study include its size and the populationbased approach increasing 4 generalizability beyond healthy volunteers in a cohort study. To the best of our knowledge, 5 6 this is the largest registerbased study to date to explore the association between dog 7 8 ownership and cardiovascular risk factors. At the same time, while national registers allow for 9 large and unselected populations with no loss to followup, we were able to include additional 10 11 clinical and health measurements and potential confounders using data from the TwinGene 12 study supporting additional confounding from employment status and nonCVD 13 14 comorbidities. Although our findings show an association between certain dog breeds and 15 16 cardiovascular riskFor factors, peer these observational review results do not only imply a causal relationship. The 17 main limitation of the study is the possibility of unmeasured confounding by demographics, 18 19 socioeconomic factors or preexisting personality traits. However, a large randomized study 20 21 of dog ownership over several years cannot be done. Further, despite adjustment for several 22 health, socioeconomic and lifestyle indicators, there is still a possibility of residual 23 24 confounding or reverse causation. For instance, we could not assess health status before pet 25 acquisition in the national cohort. A smaller study population, although not selected in 26 27 relation to exposure or outcome, and possible misclassification of dog ownership (due to no 28 29 information on partners’ dog ownership) or lifestyle questionnaire data (collected some years 30 earlier) were important limitations in the subcohort analyses. 31

32 http://bmjopen.bmj.com/ 33 Conclusion 34 35 In this large cohort study, we observed that dog ownership was associated with a minimally 36 37 higher risk of initiation of treatment for hypertension and dyslipidemia, and that ownership of 38 dogs of the hunting breed types was associated with a lower risk of initiating treatment for 39

40 diabetes. These observations may suffer from residual confounding despite access to multiple on September 29, 2021 by guest. Protected copyright. 41 42 important covariates, and future studies may add valuable information. The observed inverse 43 association of dog ownership and cardiovascular disease previously reported in this 44 45 population are unlikely to be explained by reduced hypertension and dyslipidemia. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 45 BMJ Open

13 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Acknowledgements 4 5 We acknowledge The Swedish Twin Registry for access to data. We would also like to 6 acknowledge the Swedish Kennel Club and the National Board of Agriculture for granting 7 8 access to the dog registers. They were not involved in any part of the study design, analysis, 9 10 data interpretation, manuscript preparation or approval. Support by BILS (Bioinformatics 11 Infrastructure for Life Sciences) is gratefully acknowledged. There was no compensation 12 13 received for this assistance. 14 15 Funding Statement 16 For peer review only 17 The study was funded by the Agria Research Foundation and the Swedish Research Council 18 19 for Environment, Agricultural Sciences and Spatial Planning (FORMAS), grant number 2013 20 1673. T.F has personal funding from the Goran Gustafsson foundation. The Swedish Twin 21 22 Registry is managed by Karolinska Institutet and receives funding through the Swedish 23 24 Research Council under the grant no 201700641. The funders were not involved in any part 25 of the study design, data collection, analysis manuscript preparation or approval. 26 27 Competing financial interests 28 29 30 E.I. is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to 31 the present project. The authors report that no other competing interests exist.

32 http://bmjopen.bmj.com/ 33 34 Contributorship Statement 35 T.F conceived the study and acquired funding. M.M, A.E, E.I, J.S and L.B contributed to the 36 37 design of the study. T.F. acquired the national data and P.M is responsible for the Swedish 38 39 Twin Registry data. M.M performed data cleaning. M.M and T.F ran statistical analyses. M.M

40 drafted the manuscript and all authors reviewed the manuscript. on September 29, 2021 by guest. Protected copyright. 41 42 43 44 Data sharing statement 45 46 The register data that support the findings of this study were made available by recordlinkage 47 48 49 with data from Statistics Sweden, the National Board of Health and Welfare, the Swedish 50 51 Kennel Club, Swedish Board of Agriculture and the Swedish Twin Register. Restrictions 52 53 apply to the availability of these data, which were used under license and ethical approval for 54 55 the current study, and so are not publicly available. Data are however available from the 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 45

14 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 authors upon reasonable request and with permission of the Regional Ethical Review Board in 4 5 Stockholm, Sweden. There is no additional data available. 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

†,‡

0 0 0 0 n=143 n=143 (1.4%) Hunting Hunting breeds

† 0 0 0 0 n=141 n=141 Mixed Mixed (1.3%) 60 (42.6) 60 (42.6) 64 (44.8) 61.9 (6.3) (6.3) 61.9 (6.7) 62.7 pedigree

0 0 0 0 Dog Dog (5%) (5%) n=484 n=484 owners 0 0 0 0 (95%) (95%) owners n=9,626 n=9,626 Non-dog Non-dog

All All (100%) (100%) n=10,110 n=10,110 TwinGene

†,‡

(3.2%) Hunting Hunting breeds n=65,686

† BMJ Open http://bmjopen.bmj.com/ Mixed Mixed (1.6%) 49.2 (7.1) (7.1) 49.2 (7.3) 50.0 (7.1) 63.6 (7.1) 63.7 (6.7) 62.0 n=32,003 pedigree

(14.6%) (14.6%) n=295,682 n=295,682 Dog owners Dog

on September 29, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml National Cohort Cohort National owners owners (85.4%) (85.4%) Non-dog Non-dog For n=1,731,183 peer review only

All (100%) (100%) 52.8 (8.7) (8.7) 52.8 (8.9) 53.3 (7.3) 49.9 92,043 (4.5) (4.5) 92,043 (4.7) 80,740 (228.8) 72.6 (3.8) 11,303 (315.3) 76.7 1,650 (5.2) (92.8) 49.2 2,083 (3.2) (87.7) 45.0 (106.2) 56.8 0 (111.1) 60.7 (114.7) 60.7 (72.9) 41.8 (70.3) 40.1 (68.5) 45.9 110,993 (5.5) (5.5) 110,993 (6.0) 103,645 7,348 (2.5) 1,225 (3.8) 2,346 (3.6) 445 (4.4) 420 (4.4) 25 (5.2) 7 (5.0) 9 (6.3) 129,384 (6.4) (6.4) 129,384 (7.0) 120,779 8,605 (2.9) 1,185 (3.7) 1,443 (2.2) 0 771742 (38.1) (38.1) 771742 (38.7) 669673 (34.5) 102,069 (32.1) 10,278 (35.7) 23,451 3,391 (33.5) 3,240 (33.7) 151 (31.2) 41 (29.1) 42 (29.4) n=2,026,865 n=2,026,865 985,226 (48.6) (48.6) 985,226 (48.5) 839,067 (49.4) 146,159 (52.9) 16,934 (49.9) 32,759 5,098 (50.4) 4,868 (50.6) 230 (47.5) 68 (48.2) 79 (55.2) 593,745 (29.3) (29.3) 593,745 (29.2) 506,075 (29.7) 87,670 6,678 (20.9) (35.2) 23,127 2,934 (29.0) 2,788 (29.0) 146 (30.2) 39 (27.7) 55 (38.5) 352,209 (17.4) (17.4) 352,209 (18.3) 316,728 (12.0) 35,481 7,522 (23.5) (15.7) 10,325 855 (8.5) 824 (8.6) 31 (6.4) 11 (7.8) 8 (5.6) 891,458 (44.0) (44.0) 891,458 (43.4) 751,156 (47.5) 140,302 (52.3) 16,729 (44.7) 29,352 3,107 (30.7) 2,958 (30.7) 149 (30.8) 46 (32.6) 36 (25.2) 541,662 (26.7) (26.7) 541,662 (27.4) 473,952 (22.9) 67,710 8,596 (26.9) (20.1) 13,207 4,069 (40.2) 3,880 (40.3) 189 (39.0) 56 (39.7) 52 (36.4) 269,897 (13.3) (13.3) 269,897 (12.8) 222,443 (16.0) 47,454 4,791 (15.0) 9,476 (14.4) 1,621 (16.0) 1,518 (15.8) 103 (21.3) 32 (22.7) 22 (15.4) 981,094 (48.4) (48.4) 981,094 (48.5) 839,321 (47.9) 141,773 (37.0) 11,841 (42.6) 27,961 4,189 (41.4) 3,986 (41.4) 203 (41.9) 405,175 (20.0) (20.0) 405,175 (20.0) 346,350 (19.9) 58,825 5,620 (17.6) (20.3) 13,364 405,486 (20.0) (20.0) 405,486 (20.0) 405,173 (20.1) 348,254 (20.1) 347,691 (19.4) 57,232 (19.4) 57,482 7,472 (23.3) 6,801 (21.3) (19.0) 12,461 (19.2) 12,586 1,805,438 (89.1) (89.1) 1,805,438 (88.4) 1,529,664 (93.3) 275,774 (91.1) 29,168 (94.6) 62,160 (100) 10,110 9,626 (100) 484 (100) 141 (100) 143 (100) median (IQR) inhabitant per square kilometer square per inhabitant (IQR) median

SD SD Baseline characteristics of Swedish adults aged 4580 years without cardiovascular disease according to dog ownership status (national (national status dog to ownership according disease cardiovascular without agedyears 4580 adults of Swedish characteristics Baseline ** ± ± ±±

††

Svealand Svealand 1 (lowest quintile) quintile) 1 (lowest (20.0) 405,929 (19.8) 342,412 (21.5) 63,517 8,222 (25.7) (19.3) 12,695 University University 4 4

Compulsory Compulsory Secondary 2 3 quintile) 5 (highest Sweden (20.0) 405,102 Nordic Other countries (20.0) 346,476 (19.8) 58,626 3,888 (12.1) (22.2) 14,580 Götaland countries countries Children at home home at Children (32.4) 658,355 (30.0) 521,224 (46.3) 137,131 (44.0) 14,079 (43.8) 28,785 1,500 (14.8) 1,397 (14.5) 103 (21.3) 31 (22.0) 27 (18.9) No children at home home at No children (67.6) 1,369,617 (69.9) 1,210,920 (53.7) 158,697 (56.0) 17,924 (56.2) 36,901 8,610 (85.2) 8,229 (85.5) 381 (78.7) NonNordic 110 (78.0) 116 (81.1) Norrland Divorced Divorced Widowed Widowed Married/ cohabiting cohabiting Married/ (63.0) 1,276,074 (60.4) 1,044,915 (78.2) 231,159 (59.3) 18,991 (71.0) 46,638 8,039 (79.5) 7,648 (79.5) 391 (80.8) 110 (78.0) 112 (78.3) Never married married Never (14.2) 287,589 (15.4) 265,895 (7.3) 21,694 4,265 (13.3) 6,377 (9.7) 771 (7.6) 734 (7.6) 37 (7.6) 13 (9.2) 14 (9.8)

the respective cohort are reported unless stated otherwise. stated reported are unless cohort the respective

cohort, n=2,026,865) and (TwinGene, n=10,110, responses derived from SALT study [19982002]). Age is given at baseline. Numbers and % of and Numbers given at is baseline. Age study [19982002]). SALT from derived responses n=10,110, and (TwinGene, n=2,026,865) cohort,

Country of birth Country Region of residence of Region

family of Type quintile Income density Population Exercise Male

15 15 Table 1. mean Age - Marital status Marital Education 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 15 of 45 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from Page 16 of 45 4,061 (40.2) 4,061 (40.2) 3,833 (39.8) 228 (47.1) 69 (48.9) 68 (47.6) 4,314 (42.7) 4,314 (42.7) 4,155 (43.2) 159 (32.9) 42 (29.8) 46 (32.2) 2,139 (21.2) 2,064 (21.5) 75 (15.5) 29 (20.7) 16 (11.2) 1,735 (17.2) 1,638 (17.0) 97 (20.0) 30 (21.3) 29 (20.3) 5,319 (52.8) 5,014 (52.3) 305 (63.1) 82 (58.6) 100 (69.9) 2,611 (25.9) 2,508 (26.2) 103 (21.3) 29 (20.7) 27 (18.9) BMJ Open http://bmjopen.bmj.com/

on September 29, 2021 by guest. Protected copyright.

For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Little or none or Little Average tobacco Previous user user tobacco Current tobacco tobacco Above average Above average No history of of No history ††Information on exercise levels and tobacco use was not available from the Register of the Total Population Population Total the ofRegisterthe from available not and was tobaccoexerciseon use levels ††Information **Other Nordic countries include Norway, Denmark, Iceland, Finland, the territories of the Åland Islands and the Faroe Islands and the Islands territoriesÅland of the Finland, the Iceland, Denmark, Norway, include countries Nordic **Other §Information on income not available for the TwinGene substudy in the Swedish Twin Register; Twin Register; substudy the Swedish in forTwinGene not available the income on §Information ‡Hunting breeds comprises all Terriers, Scent hounds, Pointing dog and Retriever dog breed groups. dogdog and Retriever Pointing hounds, Scent allbreeds Terriers, comprises ‡Hunting †Proportion of this breed of all ofparticipants breed of this †Proportion Use†† Tobacco clinical test at date. the ownership taken period, as and forstudy TwinGene the during time any point at haddog who registered a ownersare individuals purposes, here descriptive dog *For 16 16

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 17 of 45 BMJ Open

17 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Table 2. Association of dog ownership with initiation of medication for hypertension, 4 dyslipidemia and diabetes. For national cohort (n=2,026,865), Cox regression models with 5 hazard ratios (HR) and 95% confidence interval (CI) for incident medication are applied, 6 while logistic models for prevalent use is used in TwinGene (n=10,110) and odds ratios 7 8 presented (OR). 9 10 11 12 Cohort Medication N treated Time at risk Model 1* Model 2§ Model 3† 13 Hypertension 503,305 10,659,258 NA 14 1.02 (1.01-1.03) 1.02 (1.01-1.03) 15 National Dyslipidemia 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) NA 16 DiabetesFor peer 60,038 12,207,964review 0.91 (0.89-0.94) only 0.98 (0.951.01) NA 17 Hypertension 2,223 NA 0.96 (0.751.21) 0.94 (0.741.20) 0.90 (0.701.15) 18 TwinGene Dyslipidemia 963 NA 0.92 (0.651.29) 0.92 (0.651.29) 0.87 (0.621.22) 19 Diabetes 318 NA 0.89 (0.491.61) 0.90 (0.501.63) 0.78 (0.431.43) 20

21 22 *Model 1. Age and sex adjusted 23 24 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region 25 of birth (Sweden, Nordic, NonNordic), income, education level, latitude of residence. TwinGene: Adjusted for sex, age, type 26 of family, area of residence, population density, marital status, education level and latitude of residence 27 † Model 3. Adjusted for sex, age, number of children in the home, area of residence, population density, marital status, 28 tobacco use, occupational level, employment status, disability and Charlson comorbidity index 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

18 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Table 3. Association of dog ownership with initiation of medication for hypertension drugs, 4 dyslipidemia and diabetes by breed group in the National cohort with nondog owners as the 5 reference group. Estimates that pass Bonferroni correction for 11 breed groups (p=0.05/11) are 6 marked in bold. 7 8 9 Anti-hypertensive drugs Lipid-lowering drugs Glucose -lowering drugs 10 11 * † * † * † 12 Breed Groups Crude HR Adjusted HR Crude HR Adjusted HR Crude HR Adjusted HR 13 Sheep and cattle 14 1.04 (1.011.07) 1.03 (1.001.06) 1.01 (0.971.06) 1.01 (0.971.06) 1.03 (0.951.13) 1.06 (0.961.15) 15 dogs 16 Pinscher and For1.03 (0.991.06) peer 1.03 (1.001.07) review 1.07 (1.021.12) 1.07 only (1.02-1.12) 0.92 (0.821.02) 0.98 (0.881.09) 17 schnauzer 18 19 Terriers 0.98 (0.951.02) 0.99 (0.961.03) 1.01 (0.961.05) 1.02 (0.971.07) 0.84 (0.76-0.94) 0.91 (0.811.01) 20 21 Dachshunds 1.01 (0.961.06) 1.02 (0.971.07) 1.06 (0.991.13) 1.06 (0.991.13) 0.96 (0.841.11) 1.03 (0.891.18) 22 23 Spitz and primitive 1.05 (1.011.09) 1.00 (0.971.04) 1.04 (0.991.09) 1.01 (0.961.06) 0.82 (0.73-0.91) 0.83 (0.74-0.93) 24 types 25 Scent hounds and 26 1.05 (1.001.09) 1.03 (0.981.07) 1.07 (1.011.13) 1.05 (0.991.11) 0.86 (0.76-0.98) 0.88 (0.770.99) 27 related 28 29 Pointing dogs 0.95 (0.891.02) 0.95 (0.881.02) 0.96 (0.881.06) 0.97 (0.891.07) 0.65 (0.51-0.82) 0.73 (0.580.93) 30 31 Retrievers 1.00 (0.981.03) 1.02 (0.991.05) 1.00 (0.961.04) 1.02 (0.981.06) 0.87 (0.80-0.95) 0.98 (0.901.06)

32 http://bmjopen.bmj.com/ 33 Companion and 1.10 (1.06-1.13) 1.09 (1.05-1.12) 1.12 (1.08-1.17) 1.12 (1.07-1.16) 1.01 (0.921.12) 1.03 (0.931.14) 34 Toy dogs 35 36 Sight hounds 0.90 (0.791.02) 0.90 (0.791.02) 0.94 (0.791.12) 0.94 (0.791.12) 0.84 (0.571.26) 0.87 (0.591.30) 37

38 ‡ 39 Mixed Pedigree 1.10 (1.07-1.13) 1.07 (1.05-1.11) 1.09 (1.06-1.12) 1.09 (1.05-1.13) 1.22 (1.13-1.32) 1.18 (1.09-1.27)

40 *Adjusted for age and sex on September 29, 2021 by guest. Protected copyright. 41 †Adjusted for age, sex, marital status, presence of children in the home, population density, area of residence, education 42 level, region of birth, income and a correction for latitude of residence. 43 ‡Group comprising all nonpure pedigree dogs. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 45 BMJ Open

19 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 References 4 5 1. Levine GN, Allen K, Braun LT, et al. Pet ownership and cardiovascular risk: a scientific statement 6 from the American Heart Association. Circulation 2013;127(23):2353-63. doi: 7 10.1161/CIR.0b013e31829201e1 [published Online First: 2013/05/11] 8 2. McNicholas J, Gilbey A, Rennie A, et al. Pet ownership and human health: a brief review of 9 evidence and issues. BMJ 2005;331(7527):1252-4. doi: 10.1136/bmj.331.7527.1252 10 [published Online First: 2005/11/26] 11 3. Mubanga M, Byberg L, Nowak C, et al. Dog ownership and the risk of cardiovascular disease and 12 death - a nationwide cohort study. Sci Rep 2017;7(1):15821. doi: 10.1038/s41598-017-16118- 13 6 [published Online First: 2017/11/19] 14 4. Enmarker I, Hellzen O, Ekker K, et al. Health in older cat and dog owners: The Nord-Trondelag 15 Health Study (HUNT)-3 study. Scand J Public Health 2012;40(8):718-24. doi: 16 10.1177/1403494812465031For peer [published review Online First: 2012/12/12] only 17 5. Friedmann E, Thomas SA, Son H, et al. Pet's Presence and Owner's Blood Pressures during the Daily 18 Lives of Pet Owners with Pre- to Mild Hypertension. Anthrozoös 2013;26(4):535-50. doi: 19 10.2752/175303713X13795775536138 20 6. Hoerster KD, Mayer JA, Sallis JF, et al. Dog walking: its association with physical activity guideline 21 22 adherence and its correlates. Prev Med 2011;52(1):33-8. doi: 10.1016/j.ypmed.2010.10.011 23 [published Online First: 2010/11/05] 24 7. Lentino C, Visek AJ, McDonnell K, et al. Dog walking is associated with a favorable risk profile 25 independent of moderate to high volume of physical activity. J Phys Act Health 26 2012;9(3):414-20. [published Online First: 2011/09/22] 27 8. Parslow RA, Jorm AF. Pet ownership and risk factors for cardiovascular disease: another look. The 28 Medical journal of Australia 2003;179(9):466-8. 29 9. Utz RL. Walking the Dog: The Effect of Pet Ownership on Human Health and Health Behaviors. 30 Social Indicators Research 2014;116(2):327-39. doi: 10.1007/s11205-013-0299-6 31 10. Wright JD, Kritz-Silverstein D, Morton DJ, et al. Pet ownership and blood pressure in old age.

32 Epidemiology 2007;18(5):613-8. doi: 10.1097/EDE.0b013e3181271398 [published Online http://bmjopen.bmj.com/ 33 First: 2007/08/19] 34 11. Anderson WP, Reid CM, Jennings GL. Pet ownership and risk factors for cardiovascular disease. 35 Med J Aust 1992;157(5):298-301. [published Online First: 1992/09/07] 36 12. Leslie BE, Meek AH, Kawash GF, et al. An epidemiological investigation of pet ownership in 37 Ontario. Can Vet J 1994;35(4):218-22. [published Online First: 1994/04/01] 38 13. Flint EL, Minot EO, Perry PE, et al. Characteristics of adult dog owners in New Zealand. N Z Vet J 39 2010;58(2):69-73. doi: 10.1080/00480169.2010.65261

40 on September 29, 2021 by guest. Protected copyright. 14. Murray JK, Browne WJ, Roberts MA, et al. Number and ownership profiles of cats and dogs in the 41 42 UK. Vet Rec 2010;166(6):163-8. doi: 10.1136/vr.b4712 [published Online First: 2010/02/09] 43 15. Downes M, Canty MJ, More SJ. Demography of the pet dog and cat population on the island of 44 Ireland and human factors influencing pet ownership. Preventive veterinary medicine 45 2009;92(1-2):140-9. doi: 10.1016/j.prevetmed.2009.07.005 46 16. Westgarth C, Pinchbeck GL, Bradshaw JW, et al. Factors associated with dog ownership and 47 contact with dogs in a UK community. BMC veterinary research 2007;3:5. doi: 10.1186/1746- 48 6148-3-5 49 17. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique resource for 50 clinical, epidemiological and genetic studies. J Intern Med 2002;252(3):184-205. [published 51 Online First: 2002/09/25] 52 18. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of a 53 biobank and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. doi: 54 10.1017/thg.2012.104 [published Online First: 2012/11/10] 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 45

20 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 19. Pickup E, German AJ, Blackwell E, et al. Variation in activity levels amongst dogs of different 4 breeds: results of a large online survey of dog owners from the UK. J Nutr Sci 2017;6:e10. doi: 5 10.1017/jns.2017.7 [published Online First: 2017/06/18] 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

21 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 Figure legends: 5 6 Figure 1 - Hazard ratios (HR) and 95% confidence intervals (CI) for the association of dog ownership and time 7 to initiation of medication for hypertension, dyslipidemia and type 2 diabetes. 8 9 Figure 2 - Coefficients and 95% confidence intervals for the exposure to dog ownership compared to 10 nondog ownership on SDtransformed biochemical and clinical measurements in the TwinGene. 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 29, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 45 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 Figure 1 - Hazard ratios (HR) and 95% confidence intervals (CI) for the association of dog ownership and

40 on September 29, 2021 by guest. Protected copyright. time to initiation of medication for hypertension, dyslipidemia and type 2 diabetes stratified by age category, 41 sex and home occupancy (living alone or with someone) and adjusted for age, sex, marital status, presence 42 of children in the home, population density, area of residence, education level, region of birth, income and a 43 correction for latitude of residence. 44 45 257x265mm (72 x 72 DPI) 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 45 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Figure 2 - Coefficients and 95% confidence intervals for the exposure to dog ownership compared to nondog ownership on SD-transformed biochemical and clinical measurements in the TwinGene adjusted for

32 http://bmjopen.bmj.com/ 33 blood pressure lowering medication, lipid-lowering medication and glucose-lowering medication. 34 207x156mm (72 x 72 DPI) 35 36 37 38 39

1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Supplementary Appendix 7 8 Dog ownership and Cardiovascular Risk Factors by Mubanga et al. 9 10 11 12 Content 13 14 15 Supplementary Methods 16 Supplementary Table 1-6 17 Supplementary Figure 1-4 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Methods 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 Data Source and Parameters 6 Sweden has a structured population registration system that has enabled the collection of 7 8 individual level information on the total population. By using an identity-protected unique 9 code called the personal identity number (PIN), it is possible to link Swedish residents 10 through different national registers for information such as vital status, socio-demographic 11 data, dog ownership and health outcomes.1 12 13 Covariates 14 Covariates extracted at baseline from the Register of the Total Population included sex, birth 15 16 year, region of birth separated into Sweden, other Nordic countries and non-Nordic countries; 17 and the level of education categorized as compulsory school (≤9 years), secondary school (10- 18 11 years) and tertiaryFor education peer (≥12 years). review We further included only annually -updated covariates 19 including marital status categorized as single, married/registered partnership/cohabiting, 20 divorced or widowed; the presence of children in the home (dichotomized as yes/no), the area 21 of residence (Norrland, Svealand and Götaland), the population density in municipality of 22 residence (continuous variable), and annual household income (birth year-standardized 23 24 quintiles). A north-south gradient was adjusted for by including the latitude of the 25 municipality of residence. To avoid reverse effects of outcomes on covariates, we used 26 covariate data from the preceding year to time-update information on January 1 in every year. 27 A binary variable for home occupancy where individuals were assigned to ‘living alone’ if the 28 individual lived alone or ‘not alone’ if they were registered as living with a partner or a child. 29 Co-habiting partners with no children in common could not be accounted for via the registers. 30 Another variable for living with children aged <18 was created to account for those who lived 31 32 with children in the home. A second stratification variable was created for age group in 33 decades. 34 From the SALT study conducted in 1998-2002, we used the following self-reported variables 35 36 as covariates: age, sex, presence of children in the household, area of residence, population http://bmjopen.bmj.com/ 37 density, marital status, and latitude of residence and level of education as defined in the 38 national cohort. Additionally, we adjusted for tobacco use (never, former or current user), 39 employment status (employed, retired, sick leave or unemployed), Charlson comorbidity 40 index and disability (categorized as yes /no). Additionally the socioeconomic index which 41 ranks occupations by the average level of education and job earnings of job holders was also 42 included.2 By using National Patient Register data from the TwinGene clinic visit date to five 43 44 years prior, we created a Charlson comorbidity index. This is a widely used index for risk 3 4 on September 29, 2021 by guest. Protected copyright. 45 adjustment in health care research. 46 TwinGene 47 48 The Swedish Twin Registry is a national register started in 1958 that derives information on 49 all twin births occurring in Sweden from the National Board of Health and Welfare. It 50 contains information on more 190,000 Swedish twin pairs born from 1886 onwards.5 There 51 52 have been several sub-studies conducted within this registry that have enabled the 53 enhancement of the phenotypic and genetic data available on each participant. For this study, 54 we limited ourselves to two sub-studies that comprised participants aged 45 to 80 years and 55 who had consented to participate in both studies. Data between the two sub-studies involved 56 was collected a minimum of 2 and a maximum of 10 years apart (Supplementary Figure 2). 57 58 The first study, the Screening Across the Lifespan Twin study (SALT) interview was 59 conducted as a sub-study of the Swedish Twin Register between 1998 and 2002 targeting all 60 twin-pairs born in 1958 or earlier. Questionnaires were used to collect information on family

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1 2 3 status, occupation, education level, anthropometric measurements, alcohol intake, tobacco 4 use, environmental exposures and irritants, medication use and health - including BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 psychosocial /personality outcomes.5 Information was collected from 44,821 respondents. 6 7 The second sub-study, the TwinGene study, was nested in the previous study. Between 2004 8 and 2008 participants from SALT were invited back as part of the TwinGene Study. 9 TwinGene was set up to enable the collection of biological specimens to investigate gene- 10 11 environment interactions in participants. 12,614 invited participants gave consent to 12 participate. Questionnaires were mailed and filled in for medication use and health outcomes. 13 Blood was then collected for clinical biochemistry from a local health facility and processed 14 centrally.6 We used the date of clinic visit as the date of study. 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Table 1. Description of variables derived from the SALT questionnaire study 4 5 6 Covariate Questionnaire Option Variable created Classification and Derivative from questionnaire 7 8 Married Married, cohabiting Single Living alone 9 Marital status What is your civil status? 10 Divorced Divorced, separated, living apart 11 Widowed Widow/ widower Living in a household 12 Type of family For peerYes/ No reviewYes /No only 13 with children <18 years Primary education or less 9 years or less of education 14 Highest years of education Education level Secondary education 10 to 12 years of education 15 completed 16 Tertiary education or more More than 12 years of education http://bmjopen.bmj.com/ Employed Fully employed, part time employment, owns company, on leave from work, study 17 leave or on military service 18 Employment Employment status Retired Pensioner, prematurely retired, partly retired 19 status Retired for disability or illness Retired for injury 20 Unemployed Unemployed, housewife/man 21 Level 1 Unskilled Employees 22 Level 2 Lower skilled, non-manual workers 23 Socioeconomic Socioeconomic occupation level Level 3 Self-employed excluding independent workers 24 index Level 4 Intermediate non-manual employees on September 29, 2021 by guest. Protected copyright. 25 Level 5 Highest tier non-manual employees 26 Have you ever smoked or used Never smoked No not even tried it, yes but only tried it, smoked now and then (like at parties), 27 Tobacco Use snuff Former smoker Smoked regularly, snuffed regularly, smoke now and then (like at parties) 28 Current smoker Smoke regularly, smoke at parties, snuff now and then, snuff regularly 29 Any movement Do you have any physical Yes/no Yes/ No 30 impairment handicap 31 Do you need assistance with 32 Disability personal care/ Yes/No Yes /No 33 shopping,/cooking/mobility/ 34 Less than average Almost no exercise, light exercise, much less exercise than average, less than average 35 Regular medium exercise, average amount of exercise How much do you exercise; what 36 Exercise Average Hard physical exercise, more exercise than average, much more exercise than fits your annual exercise pattern 37 More than average normal, maximum amount of exercise 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Supplementary Table 2. Description of Breed Classification of the 331 breeds included in the study based on the Nordic Kennel Union 4 5 Classification 6 Group 7 Breed Groups Breed Designation 8 Number 9 Sheep dogs (Australian, Belgian, Catalan, German, Picardy, Polish, Portuguese, Pyrenean, Shetland, Old English); Shepherd dogs (Belgian, Bergamasco, Sheep and cattle Croatian, Dutch, German, Majorca, Polish, Romanian, South Russian); Collie (Bearded, Border, Rough, Smooth); Bouvier des Flandres, Beauceron, 1 10 dogs Briard, Chodsky Pes, Czechoslovakian Wolfdog, Komondor, Kuvasz, Mudi, Lancashire Heeler, Schipperke, Puli, Pumi, Slovakian Chuvach, Welsh 11 Corgie, Australian kelpie, Working kelpie 12 Pincher (Affenpinscher,For Austrian, peer Dobermann, German, review Miniature); Schnauzer (Giant, only Miniature); Mountain Dog (Appenzeller, Bernese, Caucasian 13 Shepherd, Entlebuch, Great Swiss, Karst, Landseer, Newfoundland, Pyrenean, Serra da Estrela, St Bernard, Uruguayan Cimarron, Yugoslavian Shepherd); Pinscher and 2 Molossian (Aidi, Anatolian Shepherd, Boxer, Bull Mastiff, Broholmer, Cane Corso, Dogo Argentino, Danish-Swedish Farm dog, Dogo Canario, Dogue de 14 schnauzer dogs 15 Bordeux, English Bulldog, Great Dane, Hovawart, Majorca Mastiff, Mastiff, Neapolitano Mastiff, Pyrenese Mastiff, Rafeiro of Alentejo, Spanish Water Dog, Shar Pei, Tosa); Central Asia Shepherd Dog, Russian Black Terrier 16 http://bmjopen.bmj.com/ Airedale, American Staffordshire, Australian, Bedlington, Border, Brazilian, Bull, Cairn, Cesky, Dandie Dinmont, English Toy, Fox, German Hunting, 17 3 Terriers Irish Glen of Imaal, Irish Softcoated Wheaten, Irish, Jack Russel, Kerry Blue, Lakeland, Manchester, Miniature Bull, Norfolk, Norwich, Parson Russell, 18 Sealyham, Australian Silky, Skye, Tenterfield, Welsh, West Highland White, Yorkshire 19 4 Dachshunds Miniature, Standard, Kaninchen 20 Alaskan Malamute, American Akita, Canaan dog, Canarian Warren, Chow Chow, Cirneco dell’Etna, East Siberian Laika, Eurasian, Finnish Lapphund, 21 Finnish Spitz, German Spitz, Greenland dog, Hokkaido, Halleforshund, Icelandic Sheepdog, Japanese Akita, Japanese Spitz, Karelian Beardog, Keeshond, Spitz and 22 5 Korea Jindo, Laponian Herder Pharaoh Hound, Mexican Hairless dog, Norwegian Buhund, Norwegian Lundehund, Norwegian Elkhound, Peruvian primitive types 23 Hairless dog, Ibizan Hound, Pomeranian, Russian European Laika, Samoyed, Shiba, Siberian Husky, Swedish Elkhound, Swedish Lapphund, Swedish

24 White Elkhound, Swedish Vallhund, Thai Bangkaew, Thai Ridgeback, Volpino italiano, West Siberian Laika, on September 29, 2021 by guest. Protected copyright. 25 Alpine Dachsbracke, American Foxhound, Basset Artesian Normand, Basset Bleu de Gascogne, Basset fauve de Bretagne, Basset Hound, Bavarian Mountain Scent hound, Beagle, Black and Tan Coonhound, Bloodhound, Bluetick Coonhound, Bosnian Coarse-haired hound, Dalmatian, Drever, Dunker 26 Scent hounds and Hound, Fawn Brittany Griffon, Finnish Hound, Foxhound, German Hound, Grand Basset Griffon Vendeen, Grand Griffon Vendeen, Griffon Nivernais, 6 27 related dogs Halden Hound, Hamilton Hound, Hygen Hound, Istrian Short-haired hound, Otterhound, Petit Basset Griffon Vendeen, Plott, Polish hunting dog, 28 Porcelain, Posavaz Hound, Rhodesian Ridgeback, Russian Hound, Russian Spotted hound, Small Blue Gascony Hound, Spanish Hound, Schiller Hound, 29 Swiss Hound, Serbian Hound, Slovakian Hound, Småland Hound 30 Blue Picardy Spaniel, Bracco Italiano, French Pointing, Brittany, Bohemian wire-haired, Drentse Patridge, English Setter, French Spaniel, Old Danish Pointer, Gordon Setter, French wire-haired Korthals Pointing Griffon, Münsterländer, Irish Red Setter, German Short/Wire-haired pointing dog, 31 7 Pointing dogs 32 Portuguese Pointing dog, Pointer, Pudelpointer, Slovakian Wire-haired Pointing dog, Italian Spinone, Stabyhound, Hungarian Vizsla wire-/short-haired, Weimaraner short-/long-haired 33 American Cocker Spaniel, Barbet, Chesapeake Bay Retriever, Clumber Spaniel, Cocker Spaniel, Curly Coated Retriever, English Springer Spaniel, Field 34 8 Retrievers Spaniel, Flat coated Spaniel, German Spaniel, Golden retriever, Irish Water Spaniel, Labrador Retriever, Lagotto romagnolo, Nederlandse Kooikerhondje, 35 Nova Scotia Duck Tolling Retriever, Spanish Water dog, Portuguese Water Dog, Sussex Spaniel, Welsh Springer Spaniel, Wetterhound Havanese, Bolognese, Boston Terrier, Belgian Griffon, Brussels Griffon, Cavalier King Charles Spaniel, Chihuahua, Chinese Crested, Coton de Tulear, 36 Companion and 9 French Bulldog, Japanese Chin, King Charles Spaniel, Kromfohrlander, Lhasa Apso, Lowchen, Maltese, Pug, Papillon, Pekingese, Small Brabant Griffon, 37 toy dogs 38 Phalene, Prazský krysarík, Poodle, Russian Toy, Shih Tzu, Tibetan Terrier, Tibetan Spaniel Afghan Hound, Azawakh, Borzoi, Polish Greyhound, Spanish Greyhound, Irish Wolfhound, Italian Greyhound, Hungarian Greyhound, Saluki, Scottish 39 10 Sight hounds Deerhound, Sloughi, Whippet 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 4 5 Supplementary Table 3. Association of dog ownership with initiation of medication for the treatment of hypertension. This compares the main 6 7 analysis as shown in Table 2 with a modified analysis that excludes Beta-blockers which have not been recommended first line treatment for 8 hypertension since XX. Cox regression models with hazard ratios (HR) and 95% confidence interval (CI) are reported. 9 10 N treated Time at risk Model 1* Model 2§ 11 12 With β-blockersFor peer503,305 review10,659,258 1.02 only (1.01-1.03) 1.02 (1.01-1.03) 13 14 Without β-blockers 401,573 11,018,086 1.03 (1.02-1.04) 1.02 (1.01-1.03) 15

16 http://bmjopen.bmj.com/ 17 18 *Model 1. Age and sex adjusted 19 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region of birth, income, education level, latitude of residence. 20 21 22 23 24 Supplementary Table 4. Association of dog ownership with initiation of lipid lowering medication. This compares on September 29, 2021 by guest. Protected copyright. the main analysis as shown 25 in Table 2 with a modified analysis that censored participants at an event of angina or heart failure. Cox regression models with hazard ratios 26 27 (HR) and 95% confidence interval (CI) are reported. 28 29 Lipid lowering N treated Time at risk Model 1* Model 2§ 30 medication 31 Without censoring 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) 32 33 With censoring 243,797 11,482,789 1.03 (1.02-1.04) 1.02 (1.01-1.04) 34 35 36 37 *Model 1. Age and sex adjusted 38 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region of birth, income, education level, latitude of residence. 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 4 5 Supplementary Table 5. Additional baseline characteristics of 10,110 Swedish adults in the Swedish Twin Register. Information is based on 6 7 persons who participated in the TwinGene project designed to enhance the Screening Across the Lifespan Twin (SALT) questionnaire-based sub- 8 study in the Swedish Twin Register with biologic specimens. Numbers and % are reported unless stated otherwise. Clinical information was 9 taken during TwinGene study (2004-2008), dog ownership status on the date of clinical examination and other non-clinical details extracted from 10 11 the SALT questionnaire (1998-2002). 12 For peer review only 13 Non-dog Mixed pedigree dog Hunting dog 14 All Dog owners owners owners owners Participant characteristics n n=10,110 n=484 15 n=9,626 n=141 n=143

(100%) (5.0%) http://bmjopen.bmj.com/ 16 (95.0%) (1.4%)* (1.4%)* 17 Employed 6,875 (68.0) 6,541 (68.0) 334 (69.0) 97 (68.8) 93 (65.0) Retired 2,066 (20.4) 1,992 (20.7) 74 (15.3) 18 (12.8) 29 (20.3) 18 Employment status 10,110 19 Sick leave or illness 875 (8.7) 818 (8.5) 57 (11.8) 18 (12.8) 16 (11.2) 20 Unemployed 294 (2.90) 275 (2.9) 19 (3.9) 8 (5.7) 5 (3.5) Unskilled labor 2,458 (24.3) 2,351 (24.4) 107 (22.1) 32 (22.7) 27 (18.9) 21 Lower non-manual labor 3,373 (33.4) 3,205 (33.3) 168 (34.7) 57 (40.4) 43 (30.1) 22 Self-employed 430 (4.3) 404 (4.2) 26 (5.4) 6 (4.3) 6 (4.2) 23 Profession† 10,110 Intermediate non-manual 2,539 (25.1) 2,411 (25.0) 128 (26.4) 32 (22.7) 46 (32.2) 24 labor on September 29, 2021 by guest. Protected copyright. Higher non-manual 25 1,310 (13.0) 1,255 (13.0) 55 (11.4) 14 (9.9) 21 (14.7) 26 employee Independent 10,100 (99.9) 9,616 (99.9) 484 (100.0) 141 (100.0) 143 (100.0) Type of housing or 27 10,110 Assisted living2 6 (0.1) 6 (0.1) 0 (0.0) 0 (0.0) 0 (0.0) accommodation 28 Other 4 (<0.0) 4 (<0.0) 0 (0.0) 0 (0.0) 0 (0.0) 29 Biochemical Variables 30 C-Reactive Protein 9,553 Median (IQR) 1.7 (0.8-3.4) 1.7 (0.8-3.4) 1.8 (0.8-3.2) 2.0 (0.9-3.5) 1.6 (0.7-3.1) 31 LDL-Cholesterol 9,727 Mean (SE) 3.9 (0.9) 3.9 (0.9) 3.8 (0.9) 3.8 (0.9) 3.9 (0.9) 32 HDL-Cholesterol 10,109 Mean 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 33 Triglyceride (Fasting) 9,261 Median 1.1 (0.8-1.6) 1.1 (0.8-1.6) 1.1 (0.9-1.6) 1.2 (0.9-1.6) 1.2 (0.9-1.5) Glucose (Non-Diabetic) 9,256 Median 5.3 (5.0-5.7) 5.3 (5.0-5.7) 5.2 (5.0-5.7) 5.3 (5.0-5.8) 5.3 (5.0-5.7) 34 35 HbA1c 10,097 Mean 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.7 (0.5) 36 Body Mass Index 9,618 Mean 25.9 (4.0) 25.9 (4.0) 26.0 (4.0) 26.3 (4.4) 26.0 (3.8) 37 Waist-Hip ratio 9,937 Mean 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 38 Blood pressure measurements Mean systolic BP (all participants) Mean 138.1 (19.5) 138.2 (19.5) 136.0 (19.2) 139.4 (20.3) 136.2 (18.1) 39 8010 Mean diastolic BP (all participants) Mean 82.2 (10.5) 82.2 (10.4) 82.6 (10.9) 84.8 (11.4) 82.7 (10.4) 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Pulse pressure (all participants) Mean 55.9 (15.4) 56.0 (15.4) 53.4 (13.6) 54.6 (13.9) 53.5 (12.5) 4 Mean systolic BP (On BP 5 Mean 144.9 (18.8) 144.9 (18.9) 144.9 (17.3) 149.4 (14.9) 142.0 (15.8) 6 treatment) Mean diastolic BP (On BP 1,970 Mean 83.9 (10.7) 83.8 (10.8) 85.0 (9.2) 84.5 (8.4) 85.6 (9.3) 7 treatment) 8 Pulse pressure (On BP treatment) Mean 61.0 (16.0) 61.1 (16.1) 60.0 (13.8) 65.0 (10.1) 56.4 (12.2) 9 Excellent 3,501 (34.9) 3,330 (34.9) 171 (35.7) 33 (23.6) 58 (40.8) Good 5,330 (53.2) 5,085 (53.3) 245 (51.1) 79 (56.4) 73 (51.4) 10 Self-reported health status 10,110 11 Average 963 (9.6) 914 (9.6) 49 (10.2) 19 (13.6) 8 (5.6) 12 Not so good 227 (2.3) 213 (2.3) 14 (2.9) 7 (5.0) 3 (2.1) Blood Pressure Medication 10,110For Number on treatmentpeer (%) 2,099review (20.8) 2,010 (20.9) only89 (18.4) 31 (22.0) 22 (15.4) 13 Lipid Modifying Medication 10,110 Number on treatment (%) 918 (9.1) 880 (9.1) 38 (7.9) 14 (9.5) 13 (8.3) 14 Diabetes Medication 10,110 Number on treatment (%) 305 (3.0) 293 (3.0) 12 (2.5) 5 (3.5) 5 (3.5) 15 16 *-Proportion of this breed of total population http://bmjopen.bmj.com/ 17 †-Defined according to Budoki et al.7 18 ‡-Assisted living which includes living in 19 BP- Blood Pressure 20 21 22 23

24 on September 29, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Supplementary Table 6. Stepwise addition of covariates into TwinGene model. Odds ratios (OR) and confidence intervals (CI) for associations 4 5 of dog ownership and prevalent drug prescriptions for hypertension, dyslipidemia and type 2 diabetes (n=10,110). * 6 7 Prescription Medication N on treatment Model 1 Model 2 Model 3 Model 4 Model 5 Model 6 Model 7 8 9 Anti-hypertensive drugs 2,223 0.96 (0.75-1.21) 0.94 (0.74-1.20) 0.95 (0.74-1.20) 0.92 (0.72-1.18) 0.90 (0.70-1.15) 0.90 (0.71-1.15) 0.90 (0.70-1.15) 10 11 Lipid lowering drugs 963 0.92 (0.65-1.29) 0.92 (0.65-1.29) 0.92 (0.66-1.29) 0.90 (0.64-1.26) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 12 For peer review only 13 Glucose lowering drugs 318 0.89 (0.49-1.61) 0.90 (0.50-1.63) 0.91 (0.50-1.65) 0.90 (0.50-1.63) 0.80 (0.44-1.46) 0.80 (0.44-1.46) 0.78 (0.43-1.43) 14 15 *Model 1, 2 and 7 were reported in the main manuscript Table 2

16 Model 1. Adjusted for age and sex http://bmjopen.bmj.com/ 17 Model 2. Adjusted for sex, age, type of family, area of residence, population density, marital status, education level and latitude of residence 18 Model 3. Model 2 plus professional level 19 Model 4. Model 3 plus employment status Model 5. Model 4 plus Charlson comorbidity index 20 Model 6. Model 5 plus disability 21 Model 7. Full twin model - Model 6 plus tobacco use 22 23

1 2 3 Supplementary Figure 1: Study population 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 7 8 3,412,946 Swedish residents aged between 45 9 and 80 years on October 1st 2006 10 11 12 13 14 15 12,105 individuals from 11,298 individuals with unverified 16 the TwinGene cohort aged or re-used identification numbers 17 and/or incomplete education 18 47-80 years For peer review only records 19

36 lipid-modifying drugs or blood factors http://bmjopen.bmj.com/ 37 glucose lowering drugs 38 39 40 41 2,026,865 eligible individuals (14.6% dog 42 owners) followed up to outcome, death, 43 emigration or study end December 31st 2012 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Fig 2: Overview of Twin Cohort study recruitment and data collection. 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Figure 3: Direct Acyclic Graph for dog ownership and cardiovascular risk. 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 The highlighted variables (comorbidity, disability and body mass index) were only available 6 in the TwinGene cohort. 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Figure 4. Hazard ratios (HR) and 95% confidence intervals (CI) for the 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 association of dog ownership and time to initiation of medication for hypertension, 6 dyslipidemia and type 2 diabetes examining associations in hunting-type breeds (combining 7 Terriers, Scent Hounds, Pointing dogs and Retrievers) and mixed pedigree dogs and adjusted 8 for age, sex, marital status, presence of children in the home, population density, area of 9 10 residence, education level, region of birth, income and a correction for latitude of residence. 11 12 13 14 15 16 Category HR (95% CI) n_events 17 18 For peer review only 19 Glucose Lowering Drugs 20 21 Hunting Breeds 0.92 (0.86, 0.97) 55490 22 Mixed Breeds 1.17 (1.09, 1.26) 55031 23 24 25 Anti-Hypertensive Drugs 26 27 Hunting Breeds 1.01 (0.99, 1.03) 464135 28 Mixed Breeds 1.08 (1.05, 1.11) 458080 29 30 31 Lipid Lowering Drugs 32 33 Hunting Breeds 1.02 (1.00, 1.05) 254860 34 Mixed Breeds 1.09 (1.05, 1.13) 251503 35 36 http://bmjopen.bmj.com/ 37 38

39 40 .8 .9 1 1.1 1.2 1.3 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 References BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 7 8 9 1. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, et al. The Swedish personal identity 10 number: possibilities and pitfalls in healthcare and medical research. European 11 journal of epidemiology 2009;24(11):659-67. doi: 10.1007/s10654-009-9350-y 12 2. Ganzeboom HB, De Graaf PM, Treiman DJ. A standard international socio-economic 13 index of occupational status. Social science research 1992;21(1):1-56. 14 3. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic 15 comorbidity in longitudinal studies: development and validation. Journal of chronic 16 17 diseases 1987;40(5):373-83. 18 4. Quan H, Li B, CourisFor CM, peer et al. Updating review and validating only the Charlson comorbidity index 19 and score for risk adjustment in hospital discharge abstracts using data from 6 20 countries. American journal of epidemiology 2011;173(6):676-82. 21 5. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique 22 resource for clinical, epidemiological and genetic studies. J Intern Med 23 2002;252(3):184-205. 24 25 6. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of 26 a biobank and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. 27 doi: 10.1017/thg.2012.104 28 7. Bukodi E, Erikson R, Goldthorpe JH. The effects of social origins and cognitive ability on 29 educational attainment. Acta Sociologica 2014;57(4):293-310. doi: 30 doi:10.1177/0001699314543803 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract Page 2 Page Abstract 2 Page Abstract 2 Page Abstract Page 5 6 5 & Page manuscript manuscript are items where reported

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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml .. Accessibility of of Accessibility and data, code protocol, raw raw protocol, programming 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 2015; 2015; PLoS Medicine Medicine PLoS BMJ Open ) license. license. ) http://bmjopen.bmj.com/ and so are not not are so and the from available upon authors request reasonable withand permission Regional of the Sweden for the current study, study, current for the available. publicly however are Data Review Ethical in Stockholm, Board CC BY on September 29, 2021 by guest. Protected copyright.

For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml in press. press. in Commons ( Attribution Creative under isprotected *Checklist Working RECORD SM, the von HT, Elm E, Sørensen Langan I, Petersen D, Moher K, Harron A, SmeethGuttmann L, EI, Benchimol *Reference: Statement. health (RECORD) Data Routinely-collected Observational using Conducted studies of REporting The Committee. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 45 of BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-023447.R1 review only Article Type: Research

Date Submitted by the 26-Jul-2018 Author:

Complete List of Authors: Mubanga, Mwenya; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory Byberg, Liisa; Uppsala Universitet, Department of Surgical Sciences, Orthopedics, Uppsala University Egenvall, Agneta; Swedish University of Agricultural Science, Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary Epidemiology Sundström, Johan; Uppsala University Magnusson, Patrik; Karolinska Institutet, Department of Medical Epidemiology and Biostatistics Ingelsson, Erik; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory; Stanford University Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, http://bmjopen.bmj.com/ Fall, Tove; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory

Primary Subject Epidemiology Heading:

Secondary Subject Heading: Cardiovascular medicine, Diabetes and endocrinology

Cardiac Epidemiology < CARDIOLOGY, EPIDEMIOLOGY, Hypertension < on September 29, 2021 by guest. Protected copyright. Keywords: CARDIOLOGY, General diabetes < DIABETES & ENDOCRINOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 51 BMJ Open

40 on September 29, 2021 by guest. Protected copyright. 41 42 43 44 *Corresponding author: Tove Fall, VMD, PhD, [email protected] 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 51

2 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Abstract (298 words; max 300) 4 5 Objective: To study the association between dog ownership and cardiovascular risk factors. 6 7 Design: A nationwide register–based cohort study and a crosssectional study in a subset. 8 9 Setting: A cohort of 2,026,865 participants was identified from the Register of the Total 10 11 Population and linked to national registers for information on dog ownership, hospital 12 13 admissions, education level, income and country of birth. Participants were followed from 14 October 1st, 2006, to the end of the study on December 31st, 2012, assessing medication for a 15 16 cardiovascular riskFor factor, emigrationpeer and review death. Crosssectional only associations were further 17 assessed in 10,110 individuals from the TwinGene study with additional adjustment for 18 19 professional level, employment status, Charlson comorbidity index, disability and tobacco 20 21 use. 22 23 Participants: All Swedish residents aged 4580 years on October 1st, 2006. 24 25 Main outcome measures: Initiation of treatment for hypertension, dyslipidemia and diabetes 26 mellitus. 27 28 29 Results 30 31 After adjustment for confounders, the results indicated slightly higher likelihood of initiating

32 antihypertensive (HR, 1.02; 95% CI, 1.011.03) and lipidlowering treatment (HR, 1.02; 95% http://bmjopen.bmj.com/ 33 34 CI, 1.011.04) in dog owners than in nonowners, particularly amongst those aged 45 to 60 35 36 and in those owning mixed breed or companion/toy breed dogs. No association of dog 37 ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 38 39 0.98; 95% CI, 0.951.01). Sensitivity analyses in the TwinGene cohort indicated confounding

40 of the association between dog ownership and prevalent treatment for hypertension, on September 29, 2021 by guest. Protected copyright. 41 42 dyslipidemia and diabetes mellitus, respectively from factors not available in the national 43 44 cohort, such as employment status and nonCVD chronic disease status. 45 46 Conclusions 47 48 In this large cohort study, dog ownership was not associated with any large reduction in 49 initiation of medication for classical cardiovascular risk factors, implying that the previously 50 51 reported lower risk of cardiovascular mortality among dog owners in this cohort is not 52 53 explained by reduced hypertension and dyslipidemia. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 51 BMJ Open

3 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Strengths and limitations of this study 4 5 • This is the largest study to date to examine the impact of dog ownership on 6 cardiovascular risk factors. 7 • The nationwide registerbased cohort study with a crosssectional investigation in a 8 9 twin registry with a vast array of lifestyle and clinical variables strengthens the results. 10 • The main outcome measures were extracted from nationwide registers thus decreasing 11 the risk of recall and selection bias. 12 Misclassification of dog ownership, particularly in the twin register, may have led to 13 • 14 some loss of power. 15 • Some important confounding factors were not available in the national data. 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Introduction 4 5 There is a growing interest in pet ownership as a possible intervention to enhance 6 7 cardiovascular health and wellbeing.[1, 2] We recently observed that being registered as a 8 dog owner was associated with a lower risk of cardiovascular and allcause mortality in the 9 10 general Swedish population (n=3,432,153).[3] Any causal association of dog ownership with 11 12 lower cardiovascular mortality could potentially be mediated through increased physical 13 activity[4, 5] or through the psychological benefits of companionship,[6] which could in turn 14 15 reduce other important cardiovascular risk factors such as blood pressure, adiposity, 16 dyslipidemia, andFor insulin resistance.[7,peer 8]review An alternative explanation only could be confounding by 17 18 socioeconomic,[9] cultural,[10] demographic[9] or psychosocial factors.[11, 12] A large 19 20 number of crosssectional and longitudinal studies across different countries support the 21 association of dog ownership with physical activity,[1] however, reports regarding the 22 23 association of dog ownership with other cardiovascular risk factors are less consistent.[1320] 24 25 These inconsistences may be due to low statistical power in small studies, use of restricted or 26 homogenous populations, inability to control for differences across breeds of dogs, or simply 27 28 an absence of effect. As dogs are reported to be more common in rural areas compared to 29 urban areas,[2123] as well as in households with children,[24, 25] it is also important to 30 31 account for these differences. The aim of this study was to assess the association of dog

32 http://bmjopen.bmj.com/ 33 ownership with three major clinical risk factors for cardiovascular disease,[26] specifically 34 initiation of treatment of hypertension, dyslipidemia and diabetes mellitus. We hypothesized 35 36 that the cardiovascular risk profile of dog owners is better than that of nondog owners. To 37 38 overcome limitations of previous studies concerning study size, generalizability and 39 differences between dog breeds, we investigated this hypothesis using data on all Swedish

40 on September 29, 2021 by guest. Protected copyright. 41 residents aged 4580 years of age in 2006 from national registers on dog ownership and drug 42 prescriptions. We further sought to explore the association with other cardiovascular risk 43 44 factors using crosssectional data from a subcohort extracted from the Swedish Twin 45 46 Registry containing detailed information from questionnaire data, physical examinations and 47 laboratory measurements. 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 51 BMJ Open

5 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Methods 4 5 Design 6 7 8 The main analysis was based on a nationwide cohort study of Swedish residents aged 4580 9 followed from October 1st 2006, to December 31st 2012. We additionally used cross 10 11 sectional data of participants (aged 4780) in the TwinGene study, which is a substudy of the 12 Swedish Twin Registry (Supplementary Figure 1). 13 14 15 Study Population – National Cohort 16 For peer review only 17 All Swedish residents (n=3,412,946) aged 4580 on October 1st 2006, were identified through 18 19 the Register of the Total Population. To ensure complete linkage to medical information and 20 sufficient information regarding dog ownership in Sweden, we excluded 11,298 individuals 21 22 with unverified, reused identification numbers or missing education information, and 23 24 137,306 additional individuals that had resided in Sweden for <15 years. We also excluded 25 531,658 individuals with a history of any CVD (International Classification of Disease (ICD) 26 27 9 codes 390459 and ICD10 I00I99) before October 1st, 2006 or with a history of coronary 28 29 artery bypass grafts or percutaneous coronary artery intervention medical procedure (Nordic 30 surgical procedure codes FNA, FNC and FNG) from in and outpatient data. Inpatient data 31

32 was available from 1987 and outpatient data from 2001. Further, using data from the Swedish http://bmjopen.bmj.com/ 33 34 Prescribed Drug Register, which covers all Swedish dispensed pharmacy prescriptions since it 35 was established on July 1st 2005, individuals (n=705,819) were excluded if they had any 36 37 recorded dispensed prescription of antihypertensive drugs, lipidlowering drugs, or glucose 38 lowering drugs from 15 months prior to baseline (which was when this register was initiated). 39

40 Antihypertensive drugs were defined based on the Anatomical Therapeutic Chemical on September 29, 2021 by guest. Protected copyright. 41 42 Classification System (ATC) as codes: C02 (antihypertensive drugs), C03A, C03EA01 43 (thiazide diuretics), C07 (beta receptor blockers, excluding sotalol [C07AA07]), C08C 44 45 (selective calcium antagonists with mainly vascular effects) and C09 (agents acting on the 46 47 reninangiotensin system). Lipidlowering drugs were defined as C10AA (statins), C10AB 48 (fibrates), C10AC (bile acid sequestrants), C10AX (other lipidmodifying agents) and C10B 49 50 (lipidlowering drug combinations). Glucoselowering drugs were defined as ATCcode 51 A10A (insulin and analogues) and A10B (glucoselowering drugs excluding insulin). 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 51

6 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Study population – TwinGene 4 5 The TwinGene study originally included 12,614 (of 22,391 invited) twins from the 6 7 “Screening Across the Lifespan Twin study” (SALT) was conducted between April 2004 and 8 December 2008 and included a visit to their local health center and blood sampling 9 10 (Supplementary Figure 2).[27] The studybase “SALT” was a substudy of the Swedish 11 12 Twin Register in twins born before 1959 and who participated in a telephonebased 13 questionnaire substudy from March 1998 to March 2002[27] (Supplementary Table 1). 14 15 16 We performed a Forcrosssectional peer analysis reviewof the association of only dog ownership with 17 cardiovascular risk factors in the TwinGene cohort (n=12,105). We excluded 1,373 18 19 individuals for having a previous history of CVD recorded in the National Patient 20 21 Register.[28] We also excluded 622 individuals for having missing or incomplete data 22 (Supplementary Figure 1). 23 24 25 Exposure 26 27 Dogs in Sweden are required to have a unique identifier (ear tattoo or implanted identity chip) 28 29 and this is registered alongside their owner’s unique personal identity number at the Swedish 30 Board of Agriculture. All dogs sold as purebred are registered by the Swedish Kennel Club. 31 We defined the variable ‘dog ownership’ in the national cohort as registered dog ownership or 32 http://bmjopen.bmj.com/ 33 having a partner registered as a dog owner in either the Swedish Board of Agriculture and/or 34 35 the Swedish Kennel Club. Exposure to dog ownership was timeupdated to include only those 36 37 periods where each dog was alive and registered to the study participant or their registered 38 partner. The identification of partners was possible through annual extracts from the Register 39

40 of the Total Population that keeps track of couples that are married, registered in samesex on September 29, 2021 by guest. Protected copyright. 41 42 partnership or are cohabiting with common children. 43 44 In the TwinGene data, we did not have access to information on partners’ dog ownership and 45 46 only each person’s own dog registrations were used. Dog ownership was defined at the date 47 of inclusion in TwinGene. 48 49 50 If information on a dog’s death was missing, we assumed a maximum lifespan of ten 51 years.[29] We conducted sensitivity analyses examining associations with dog death at a 52 53 maximum lifespan of 8 years and 12 years. Where birth or registration dates were discrepant 54 between the two registers, we randomly selected one of the two. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 51 BMJ Open

7 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 To define breed groups, we used the Federation Cynologique International standard with 4 some local adaption from Swedish Kennel Club’s definition to categorize the 331 breeds into 5 6 ten breed groups based on character and behaviour attributes (Supplementary Table 2). All 7 8 nonpurebred dogs and those of unknown breed were included in an additional mixed breed 9 group. Where owners had dogs of different breeds, we defined the breed based on the dog 10 11 registered first and where owners had several dogs, we restricted ownership to three dogs. 12 13 Based on previous findings of owners to hunting dogs having a lower risk of cardiovascular 14 15 events,[3] we additionally defined a group of hunting dogs consisting of Terriers, Pointing, 16 Scent Hounds andFor Retrievers peer for analysis. review only 17 18 19 Outcome 20 21 In the national cohort, time to first dispensed prescription of antihypertensive drugs, lipid 22 23 lowering drugs or glucoselowering drugs after baseline was defined from data extracted from 24 25 the drug register. Each outcome was considered separately as we chose to estimate the total 26 effect of dog ownership and not only the direct effects. Participants were censored at 27 28 emigration, death or at the end of the study on December 31st, 2012. In the analysis of time to 29 antihypertensive medication, individuals were additionally censored at a diagnosis of heart 30 31 failure, unstable angina or acute myocardial infarction in the National Patient Register as the

32 http://bmjopen.bmj.com/ 33 same drugs could be administered for their treatment. 34 35 Prevalent use of antihypertensive, lipidlowering or glucoselowering drugs was defined 36 37 from the clinical questionnaire data collected during the TwinGene study. Cardiovascular risk 38 factors measured and also used as outcomes in TwinGene included blood glucose, 39

40 glycosylated hemoglobin A1c (HbA1c), high sensitive Creactive protein (hsCRP), on September 29, 2021 by guest. Protected copyright. 41 42 triglycerides, high density lipoproteincholesterol (HDLC), low density lipoprotein 43 cholesterol (LDLC), waisthip ratio, body mass index (BMI), systolic and diastolic blood 44 45 pressure and mean arterial pressure (MAP) (Supplementary methods). Only fasting 46 measurements of glucose and triglycerides were used (9,873 [97%] of all participants were 47 48 fasting). 49 50

51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 51

8 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Statistical analyses 4 5 All statistical analyses were conducted using Stata version MP14.1 (StataCorp). 6 7 8 Using age as a timescale, separate multivariable Cox proportional hazards models were 9 applied to assess the associations between dog ownership and time to initiation of anti 10 11 hypertensive, lipidlowering and glucoselowering drugs, respectively. Directed acyclic 12 graphs were used to guide the choice of covariates (Supplementary Figure 3). A first crude 13 14 model included age and sex, and a second model additionally included the region of birth, 15 16 area of residence,For latitude ofpeer residence, populationreview density, levelonly of education, marital status, 17 presence of children in the home and income. A description of the covariates is provided in 18 19 the Supplementary methods. The proportional hazards assumption was verified by plotting 20 21 Schoenfield residuals and loglog graphs. Results were reported as hazard ratios (HR) and 22 95% confidence intervals (CI). We repeated the calculations using the breed group as 23 24 exposure to examine possible breed group effects and we applied Bonferroni correction (for 25 11 breed groups) to control for multiple testing. Further analyses were stratified by age group, 26 27 sex, and whether participants lived alone or not. Individuals considered as “living alone” did 28 29 not have any spouse, partner with common children, or children living in the same household. 30 31 We conducted a sensitivity analysis where we excluded βblockers as first line anti

32 http://bmjopen.bmj.com/ 33 hypertensive treatment to estimate the effect of changing treatment guidelines over the study 34 period. In additional sensitivity analysis, in the lipidlowering medication analysis, we 35 36 assessed the effect of censoring participants at a diagnosis of heart failure, unstable angina or 37 38 acute myocardial infarction in the National Patient Register. 39

40 Logistic regression was applied in TwinGene for the association of dog ownership with on September 29, 2021 by guest. Protected copyright. 41 42 prevalent antihypertensive, lipidlowering and bloodglucose lowering medication and linear 43 regression for the association of dog ownership with continuous variables. hsCRP and 44 45 triglycerides were transformed to the natural log scale before analysis to approach normality. 46 In addition to adjusting for age, sex, presence of children in the household, area of residence, 47 48 population density, marital status, latitude of residence and level of education, we added 49 50 further covariates, one at a time to investigate their individual importance: tobacco use, 51 occupational level, employment status, Charlson comorbidity index and disability. In all twin 52 53 analyses, standard errors were adjusted with the robust sandwich estimator for dependent 54 55 observations. For blood pressure and lipid levels, associations were further stratified by 56 current medication. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 51 BMJ Open

9 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Ethical approval 4 5 The regional ethical review board in Stockholm, Sweden, approved the study (national study: 6 7 2012/111431/2, with amendment 2013168732; TwinGene: 2007/64431/2 and 2016/1392 8 31/1). 9 10 11 Patient involvement 12 13 No patients were involved in the development, design or analysis of this study. The review 14 15 board allowed the researchers to waive the requirement for obtaining informed consent in the 16 national study. ParticipantsFor peer in TwinGene review provided written informed only consent. 17 18 19 Results 20 21 National Cohort 22 23 The baseline characteristics of 2,026,865 Swedish residents are shown in Table 1. Dog 24 25 ownership was directly registered in 189,355 (9.3%) at any time during the followup period, 26 27 and this increased to 295,682 (14.6%) individuals when partners’ registration were included. 28 At baseline, the average age of dog owners was 50 years vs 53 years in nonowners. Dog 29 30 owners were more likely to be married than nonowners (78% vs 60%) and more likely to live 31 in lowdensity areas than nonowners (median: 49 vs 77 inhabitants per square kilometer).

32 http://bmjopen.bmj.com/ 33 Compared to nonowners, mixed pedigree dog owners (n=32,003) were less likely to be 34 35 married (59 %), were less likely to have a tertiary education (21%) and had fewer people in 36 the top quintile for income (12.2%). Owners of huntingtype breeds showed similar 37 38 characteristics to the overall dog owners. 39

40 Medication for cardiovascular risk factors on September 29, 2021 by guest. Protected copyright. 41 42 During 10,692,258 personyears of followup, dog ownership was associated with a 2% 43 44 higher risk of initiation of antihypertensive drug medication in both crude and multivariable 45 46 adjusted analyses (HR, 1.02; 95% CI, 1.011.03). During 11,508,349 personyears of follow 47 up, there was a 2% higher risk of initiating lipidlowering medication in the multivariable 48 49 adjusted models (HR, 1.02; 95% CI, 1.011.04). During 12,207,964 personyears of follow 50 51 up, there was a lower risk of initiating glucose lowering drugs in dog owners in minimally 52 adjusted models (HR, 0.91; 95% CI, 0.890.94), but on multivariable adjustment, the 53 54 association was attenuated and nonsignificant (HR, 0.98; 95% CI, 0.951.01) (Table 2). 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 51

10 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Owners of “Companion/toy” breeds and of dogs of mixed pedigree were at higher risk of anti 4 hypertensive and lipidlowering drug initiation compared to nondog owners (Table 3). 5 6 Owners of the Spitz/primitive breed types and the combined group of hunting breed types had 7 8 lower risks of initiating glucoselowering medication (HR, 0.83; 95% CI, 0.740.93 and HR, 9 0.92; 95% CI, 0.860.97 respectively), while owners of mixed pedigree dogs had higher risk 10 11 of getting glucoselowering medication (HR, 1.17; 95% CI, 1.091.26) (Supplementary 12 Figure 4). 13 14 15 There was no difference in strength of association when we excluded βblockers as firstline 16 treatment for antihypertensionFor peer (Supplementary review Table 3) or only when censoring was done in 17 18 those being investigated for lipidlowering treatment initiation was made for angina, 19 myocardial infarction or heart failure was conducted (Supplementary Table 4). 20 21 22 In agestratified analysis, there were some evidence of effect modification by age for both 23 antihypertensive and lipidlowering drugs where an increased risk was observed in those 24 25 aged below 50 years (HR, 1.04; 95% CI, 1.011.08 and HR, 1.10; 95% CI, 1.041.15, 26 respectively), with estimates gradually approaching one with increasing age (Figure 1). 27 28 Inverse associations of dog ownership with glucoselowering drugs was observed in the lower 29 30 age groups, in males and those not living alone (HR, 0.89; 95% CI, 0.790.99, HR, 0.95; 95% 31 CI, 0.920.99 and HR, 0.91; 95% CI, 0.860.97, respectively).

32 http://bmjopen.bmj.com/ 33 TwinGene 34 35 On crosssectional analysis of 10,110 individuals, 484 (5%) were registered as dog owners 36 37 (partners’ dogs not included) and their characteristics are described in Table 1 and 38 39 Supplementary Table 5. Using similar covariates as in the national cohort, no association of

40 dog ownership was found with prevalent use of antihypertensive drugs (OR, 0.94; 95% CI, on September 29, 2021 by guest. Protected copyright. 41 42 0.741.20), lipidlowering drugs (OR, 0.92; 95% CI, 0.651.29) or glucoselowering drugs 43 44 (OR, 0.90; 95% CI, 0.501.63) (Table 2). Upon inclusion of additional covariates, the 45 Charlson comorbidity index and the employment status were found to be the most influential 46 47 confounders and the fully adjusted model yielded lower but still nonsignificant estimates: 48 OR, 0.90 (95% CI, 0.701.15) for use of antihypertensive drugs, OR, 0.87 (95% CI, 0.62 49 50 1.22) for lipidlowering drugs and OR, 0.78 (95% CI, 0.431.43) for glucoselowering drugs 51 52 (Supplementary Table 6). We found no association between dog ownership and the other 53 clinical and biochemical cardiovascular risk factors (Figure 2). 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 51 BMJ Open

11 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Sensitivity analyses on changing the maximum lifespan of dogs in the national cohort that had 4 no dates of death to 8 years or 12 years yielded similar results to the maximum of 10 years 5 6 used in the main analysis (Supplementary Table 7). To provide additional information, the 7 8 output from the fully adjusted Cox regression models for the association of dog ownership 9 with the initiation of medication for hypertension, dyslipidemia and diabetes mellitus in the 10 11 national cohort are included in the supplementary material as Supplementary Table 8, 12 Supplementary Table 9 and Supplementary Table 10, respectively. 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

12 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Discussion 4 5 In this nationwide study in a population without previous cardiovascular disease, we observed 6 7 a minimally higher risk of initiation of treatment for hypertension and dyslipidemia among 8 persons with a dog in their household compared to those without dogs in the household. 9 10 Associations were most prominent in younger age groups (4060 years). Owning a dog of 11 12 mixed pedigree or a dog belonging to the “companion/toy” breed group was associated with 13 hypertension and dyslipidemia, whilst ownership of a dog from the “Spitz/primitive” breed 14 15 and the combined group of huntingtype breeds (Terriers, Pointing, Scent Hounds and 16 Retrievers) was associatedFor peerwith lower risk review of treatment for diabetesonly mellitus. Crosssectional 17 18 analyses in 10,110 participants from TwinGene showed no association of dog ownership with 19 20 body mass index, waisttohipratio, blood pressure or biochemical cardiovascular risk 21 factors, and indicated that the association of dog ownership with medication for hypertension, 22 23 dyslipidemia and diabetes was confounded by employment status and nonCVDchronic 24 25 conditions. This suggests that the slightly higher associations observed in the national cohort 26 would potentially be attenuated in the presence of the additional confounders. 27 28 29 That owners of mixedbreed and “companion/toy” breeds, as well as dog owners in younger 30 age groups, had mildly increased risks for hypertension and dyslipidemia are in line with our 31

32 previous study regarding higher risk of myocardial infarction and stroke in this group. The http://bmjopen.bmj.com/ 33 level of dog walking might be lower in the smaller companion/toy dogs breeds as compared 34 35 to the huntingtype breeds.[30] In TwinGene, 68% of hunting breed owners reporting a high 36 37 level of physical activity versus 52% in nondog owners.[30] We note that the proportion of 38 highest education level in the mixed breed group was remarkably lower than the general 39

40 population (20.9% vs 29.3%). Although we adjusted for educational level, it is likely that on September 29, 2021 by guest. Protected copyright. 41 42 there is unmeasured confounding from differences in healthseeking behavior, smoking habits 43 or stress in dogowners in working age groups. In TwinGene, we noted that additional 44 45 adjustment for employment status (unemployed, retired, sick leave or unemployed) and a 46 comorbidity index (for diseases other than CVD) were important confounders lowering the 47 48 estimates. These covariates were not available in the national cohort, implying that the results 49 50 in the national cohort are likely to have been confounded by these or other factors. 51 52 Our findings in TwinGene are different from an Australian cohort study in 5,741 individuals 53 54 with 13.6% pet ownership who found lower levels of plasma cholesterol, triglycerides and 55 systolic blood pressures in petowners than nonowners.[20] Dog owners (6.3%) had better 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 51 BMJ Open

13 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 selfrated health but no difference in blood pressure than nonpet owners in crosssectional 4 analysis of the NordTrondelag Health Study (HUNT)3 study (n=12,297).[13] 5 6 7 There are a limited number of studies of the association between dog ownership and the risk 8 of type 2 diabetes. A study by Lentino et al., (n=916) showed that regular dog walkers 9 10 (n=399, 44%) in a primarily welleducated Caucasian population had lower BMI and were at 11 12 lower risk of both dyslipidemia and type 2 diabetes than other study participants.[16] These 13 findings were contradicted by Wright et al, who showed that dog owners were more likely to 14 15 be overweight, and have diabetes than nonowners in a study of 1179 community dwellers 16 with 30% pet ownership.[19]For peer Differences review in findings across countriesonly could be due to 17 18 differences in study design, or to inherent differences in dog management and the type of dog 19 20 breeds in the country. 21 22 A previous study in this population showed a lower risk of cardiovascular disease and all 23 24 cause mortality in dog owners.[3] The current study suggests that it is unlikely that 25 hypertension and dyslipidemia mediates these effects. Other potential factors that may explain 26 27 this reduction in mortality include increased social wellbeing and decreased psychological 28 29 stress.[31] 30 31 Strengths and weaknesses

32 http://bmjopen.bmj.com/ 33 The main strengths of our study include its size and the populationbased approach increasing 34 35 generalizability beyond healthy volunteers in a cohort study. To the best of our knowledge, 36 37 this is the largest registerbased study to date to explore the association between dog 38 ownership and cardiovascular risk factors. At the same time, while national registers allow for 39

40 large and unselected populations with no loss to followup, they lack information on on September 29, 2021 by guest. Protected copyright. 41 42 individual attributes such body mass index, blood pressure, lipid levels and physical activity. 43 A strength of this study is that we were able to include additional clinical health 44 45 measurements and socioeconomic variables using data from the TwinGene study supporting 46 the presence of additional confounding of the relationship between dog ownership and 47 48 cardiovascular risk factors from employment status and nonCVD comorbidities. Although 49 50 our findings show an association between certain dog breeds and cardiovascular risk factors, 51 these observational results do not imply a causal relationship. 52 53 54 The main limitation of the study is the possibility of remaining unmeasured confounding by 55 unmeasured socioeconomic factors or preexisting personality traits. Further the register 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 51

14 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 based nature of our study made it impossible for us to account for petassociated factors such 4 as primary pet responsibility, physical activity, the level of dog attachment or indeed the 5 6 reason for acquiring a dog. Physical activity related to dog walking may however be a 7 8 mediator of the association between dog ownership and health outcomes and separating 9 activity performed in relation to dog walking and other types of activity would be important. 10 11 However, a large randomized study of dog ownership over several years cannot be done. 12 Further, despite adjustment for several health, socioeconomic and lifestyle indicators, there is 13 14 still a possibility of residual confounding or reverse causation. For instance, we could not 15 16 assess health statusFor before peerpet acquisition review in the national cohort. only A smaller study population, 17 although not selected in relation to exposure or outcome, and possible misclassification of dog 18 19 ownership (due to no information on partners’ dog ownership) or lifestyle questionnaire data 20 21 (collected some years earlier) were important limitations in the subcohort analyses. 22 Misclassification of dog ownership was also possible in cohabiting partners without children 23 24 in common as these would not be registered as cohabiting in the Register of The Total 25 Population. Another important limitation is that we were unable to account for those that did 26 27 not initiate treatment due to any of the three conditions. The Prescribed Drug Register does 28 29 not keep a record of adherence to treatment or records of those prescribed lifestyle 30 interventions such as diet or exercise. 31

15 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Acknowledgements 4 5 We acknowledge The Swedish Twin Registry for access to data. We would also like to 6 acknowledge the Swedish Kennel Club and the National Board of Agriculture for granting 7 8 access to the dog registers. They were not involved in any part of the study design, analysis, 9 10 data interpretation, manuscript preparation or approval. Support by BILS (Bioinformatics 11 Infrastructure for Life Sciences) is gratefully acknowledged. There was no compensation 12 13 received for this assistance. 14 15 Funding Statement 16 For peer review only 17 The study was funded by the Agria Research Foundation and the Swedish Research Council 18 19 for Environment, Agricultural Sciences and Spatial Planning (FORMAS), grant number 2013 20 1673. T.F has personal funding from the Goran Gustafsson foundation. The Swedish Twin 21 22 Registry is managed by Karolinska Institutet and receives funding through the Swedish 23 24 Research Council under the grant no 201700641. The funders were not involved in any part 25 of the study design, data collection, analysis manuscript preparation or approval. 26 27 Competing financial interests 28 29 30 E.I. is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to 31 the present project. The authors report that no other competing interests exist.

16 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 authors upon reasonable request and with permission of the Regional Ethical Review Board in 4 5 Stockholm, Sweden. There is no additional data available. 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

†,‡

0 0 0 0 n=143 n=143 (1.4%) Hunting Hunting breeds

† 0 0 0 0 n=141 n=141 Mixed Mixed (1.3%) 60 (42.6) 60 (42.6) 64 (44.8) 61.9 (6.3) (6.3) 61.9 (6.7) 62.7 pedigree

0 0 0 0 Dog Dog (5%) (5%) n=484 n=484 owners 0 0 0 0 (95%) (95%) owners n=9,626 n=9,626 Non-dog Non-dog

All All (100%) (100%) n=10,110 n=10,110 TwinGene

†,‡

2,139 (21.2) 2,064 (21.5) 75 (15.5) 29 (20.7) 16 (11.2) (3.2%) Hunting Hunting breeds n=65,686

† BMJ Open http://bmjopen.bmj.com/ Mixed Mixed (1.6%) 49.2 (7.1) (7.1) 49.2 (7.3) 50.0 (7.1) 63.6 (7.1) 63.7 (6.7) 62.0 n=32,003 pedigree

(14.6%) (14.6%) n=295,682 n=295,682 Dog owners Dog

on September 29, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml National Cohort Cohort National owners owners (85.4%) (85.4%) Non-dog Non-dog For n=1,731,183 peer review only

All (100%) (100%) 52.8 (8.7) (8.7) 52.8 (8.9) 53.3 (7.3) 49.9 92,043 (4.5) (4.5) 92,043 (4.7) 80,740 (3.8) 11,303 1,650 (5.2) 2,083 (3.2) 0 72.6 (228.8) (228.8) 72.6 (315.3) 76.7 (92.8) 49.2 (87.7) 45.0 (106.2) 56.8 (111.1) 60.7 (114.7) 60.7 (72.9) 41.8 (70.3) 40.1 (68.5) 45.9 110,993 (5.5) (5.5) 110,993 (6.0) 103,645 7,348 (2.5) 1,225 (3.8) 2,346 (3.6) 445 (4.4) 420 (4.4) 25 (5.2) 7 (5.0) 9 (6.3) 129,384 (6.4) (6.4) 129,384 (7.0) 120,779 8,605 (2.9) 1,185 (3.7) 1,443 (2.2) 0 771742 (38.1) (38.1) 771742 (38.7) 669673 (34.5) 102,069 (32.1) 10,278 (35.7) 23,451 3,391 (33.5) 3,240 (33.7) 151 (31.2) 41 (29.1) 42 (29.4) n=2,026,865 n=2,026,865 985,226 (48.6) (48.6) 985,226 (48.5) 839,067 (49.4) 146,159 (52.9) 16,934 (49.9) 32,759 5,098 (50.4) 4,868 (50.6) 230 (47.5) 68 (48.2) 79 (55.2) 593,745 (29.3) (29.3) 593,745 (29.2) 506,075 (29.7) 87,670 6,678 (20.9) (35.2) 23,127 2,934 (29.0) 2,788 (29.0) 146 (30.2) 39 (27.7) 55 (38.5) 352,209 (17.4) (17.4) 352,209 (18.3) 316,728 (12.0) 35,481 7,522 (23.5) (15.7) 10,325 855 (8.5) 824 (8.6) 31 (6.4) 11 (7.8) 8 (5.6) 541,662 (26.7) (26.7) 541,662 (27.4) 473,952 (22.9) 67,710 8,596 (26.9) (20.1) 13,207 4,069 (40.2) 3,880 (40.3) 189 (39.0) 56 (39.7) 52 (36.4) 891,458 (44.0) (44.0) 891,458 (43.4) 751,156 (47.5) 140,302 (52.3) 16,729 (44.7) 29,352 3,107 (30.7) 2,958 (30.7) 149 (30.8) 46 (32.6) 36 (25.2) 269,897 (13.3) (13.3) 269,897 (12.8) 222,443 (16.0) 47,454 4,791 (15.0) 9,476 (14.4) 1,621 (16.0) 1,518 (15.8) 103 (21.3) 32 (22.7) 22 (15.4) 405,173 (20.0) (20.0) 405,173 (20.1) 347,691 (19.4) 57,482 6,801 (21.3) (19.2) 12,586 405,486 (20.0) (20.0) 405,486 (20.0) 405,175 (20.1) 348,254 (20.0) 346,350 (19.4) 57,232 (19.9) 58,825 7,472 (23.3) (19.0) 12,461 5,620 (17.6) (20.3) 13,364 981,094 (48.4) (48.4) 981,094 (48.5) 839,321 (47.9) 141,773 (37.0) 11,841 (42.6) 27,961 4,189 (41.4) 3,986 (41.4) 203 (41.9) 1,805,438 (89.1) (89.1) 1,805,438 (88.4) 1,529,664 (93.3) 275,774 (91.1) 29,168 (94.6) 62,160 (100) 10,110 9,626 (100) 484 (100) 141 (100) 143 (100) median (IQR) inhabitant per square kilometer square per inhabitant (IQR) median

†† Other Nordic Nordic Other countries 3 3 Children at home home at Children (32.4) 658,355 Compulsory University (30.0) 521,224 quintile) 1 (lowest (46.3) 137,131 2 (44.0) 14,079 (20.0) 405,929 4 (43.8) 28,785 quintile) 5 (highest (19.8) 342,412 Sweden 1,500 (14.8) (20.0) 405,102 (21.5) 63,517 1,397 (14.5) (20.0) 346,476 8,222 (25.7) 103 (21.3) (19.8) 58,626 (19.3) 12,695 31 (22.0) 3,888 (12.1) (22.2) 14,580 Svealand 27 (18.9) Götaland none or Little countries countries Secondary Secondary No children at home home at No children (67.6) 1,369,617 (69.9) 1,210,920 (53.7) 158,697 (56.0) 17,924 (56.2) 36,901 8,610 (85.2) 8,229 (85.5) 381 (78.7) NonNordic 110 (78.0) 116 (81.1) Norrland Married/ cohabiting cohabiting Married/ (63.0) 1,276,074 Divorced Widowed (60.4) 1,044,915 (78.2) 231,159 (59.3) 18,991 (71.0) 46,638 8,039 (79.5) 7,648 (79.5) 391 (80.8) 110 (78.0) 112 (78.3) Never married married Never (14.2) 287,589 (15.4) 265,895 (7.3) 21,694 4,265 (13.3) 6,377 (9.7) 771 (7.6) 734 (7.6) 37 (7.6) 13 (9.2) 14 (9.8)

the respective cohort are reported unless stated otherwise. stated reported are unless cohort the respective

Type of family of Type cohort, n=2,026,865) and (TwinGene, n=10,110, responses derived from SALT study [19982002]). Age is given at baseline. Numbers and % of and Numbers given at is baseline. Age study [19982002]). SALT from derived responses n=10,110, and (TwinGene, n=2,026,865) cohort, Exercise

Education quintile Income of birth Country density Population residence of Region Male Male

17 17 Table 1. mean Age - Marital status Marital

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 17 of 51 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from Page 18 of 51 4,314 (42.7) 4,314 (42.7) 4,155 (43.2) 159 (32.9) 42 (29.8) 46 (32.2) 4,061 (40.2) 4,061 (40.2) 3,833 (39.8) 228 (47.1) 69 (48.9) 68 (47.6) 1,735 (17.2) 1,638 (17.0) 97 (20.0) 30 (21.3) 29 (20.3) 5,319 (52.8) 5,014 (52.3) 305 (63.1) 82 (58.6) 100 (69.9) 2,611 (25.9) 2,508 (26.2) 103 (21.3) 29 (20.7) 27 (18.9) BMJ Open http://bmjopen.bmj.com/

on September 29, 2021 by guest. Protected copyright.

For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Current tobacco user user tobacco Current Average Average Above average tobacco Previous user tobacco tobacco No history of of No history

Tobacco Use†† Use†† Tobacco ††Information on exercise levels and tobacco use was not available from the Register of the Total Population Population Total the ofRegisterthe from available not and was tobaccoexerciseon use levels ††Information **Other Nordic countries include Norway, Denmark, Iceland, Finland, the territories of the Åland Islands and the Faroe Islands and the Islands territoriesÅland of the Finland, the Iceland, Denmark, Norway, include countries Nordic **Other §Information on income not available for the TwinGene substudy in the Swedish Twin Register; Twin Register; substudy the Swedish in forTwinGene not available the income on §Information ‡Hunting breeds comprises all Terriers, Scent hounds, Pointing dog and Retriever dog breed groups. dogdog and Retriever Pointing hounds, Scent allbreeds Terriers, comprises ‡Hunting †Proportion of this breed of all ofparticipants breed of this †Proportion clinical test at date. the ownership taken period, as and forstudy TwinGene the during time any point at haddog who registered a ownersare individuals purposes, here descriptive dog *For 18 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 19 of 51 BMJ Open

19 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Table 2. Association of dog ownership with initiation of medication for hypertension, 4 dyslipidemia and diabetes. For national cohort (n=2,026,865), Cox regression models with 5 hazard ratios (HR) and 95% confidence interval (CI) for incident medication are applied, 6 while logistic models for prevalent use is used in TwinGene (n=10,110) and odds ratios 7 8 presented (OR). 9 10 Cohort Medication N treated Time at risk Model 1* Model 2§ Model 3† 11 12 Hypertension 503,305 10,659,258 1.02 (1.01-1.03) 1.02 (1.01-1.03) NA 13 National Dyslipidemia 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) NA 14 Diabetes 60,038 12,207,964 0.91 (0.89-0.94) 0.98 (0.951.01) NA 15 Hypertension 2,223 NA 0.96 (0.751.21) 0.94 (0.741.20) 0.90 (0.701.15) 16 TwinGene DyslipidemiaFor peer 963 review NA 0.92 (0.651.29) only 0.92 (0.651.29) 0.87 (0.621.22) 17 18 Diabetes 318 NA 0.89 (0.491.61) 0.90 (0.501.63) 0.78 (0.431.43) 19 20 *Model 1. Age and sex adjusted 21 22 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region 23 of birth (Sweden, Nordic, NonNordic), income, education level, latitude of residence. TwinGene: Adjusted for sex, age, type 24 of family, area of residence, population density, marital status, education level and latitude of residence 25 26 † Model 3. Adjusted for sex, age, number of children in the home, area of residence, population density, marital status, 27 tobacco use, occupational level, employment status, disability and Charlson comorbidity index 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

20 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Table 3. Association of dog ownership with initiation of medication for hypertension drugs, 4 dyslipidemia and diabetes by breed group in the National cohort with nondog owners as the 5 reference group. Estimates that pass Bonferroni correction for 11 breed groups (p=0.05/11) are 6 marked in bold. 7 8 9 Anti-hypertensive drugs Lipid-lowering drugs Glucose -lowering drugs 10 11 * † * † * † 12 Breed Groups Crude HR Adjusted HR Crude HR Adjusted HR Crude HR Adjusted HR 13 Sheep and cattle 14 1.04 (1.011.07) 1.03 (1.001.06) 1.01 (0.971.06) 1.01 (0.971.06) 1.03 (0.951.13) 1.06 (0.961.15) 15 dogs 16 Pinscher and For1.03 (0.991.06) peer 1.03 (1.001.07) review 1.07 (1.021.12) 1.07 only (1.02-1.12) 0.92 (0.821.02) 0.98 (0.881.09) 17 schnauzer 18 19 Terriers 0.98 (0.951.02) 0.99 (0.961.03) 1.01 (0.961.05) 1.02 (0.971.07) 0.84 (0.76-0.94) 0.91 (0.811.01) 20 21 Dachshunds 1.01 (0.961.06) 1.02 (0.971.07) 1.06 (0.991.13) 1.06 (0.991.13) 0.96 (0.841.11) 1.03 (0.891.18) 22 23 Spitz and primitive 1.05 (1.011.09) 1.00 (0.971.04) 1.04 (0.991.09) 1.01 (0.961.06) 0.82 (0.73-0.91) 0.83 (0.74-0.93) 24 types 25 Scent hounds and 26 1.05 (1.001.09) 1.03 (0.981.07) 1.07 (1.011.13) 1.05 (0.991.11) 0.86 (0.76-0.98) 0.88 (0.770.99) 27 related 28 29 Pointing dogs 0.95 (0.891.02) 0.95 (0.881.02) 0.96 (0.881.06) 0.97 (0.891.07) 0.65 (0.51-0.82) 0.73 (0.580.93) 30 31 Retrievers 1.00 (0.981.03) 1.02 (0.991.05) 1.00 (0.961.04) 1.02 (0.981.06) 0.87 (0.80-0.95) 0.98 (0.901.06)

38 ‡ 39 Mixed Pedigree 1.10 (1.07-1.13) 1.07 (1.05-1.11) 1.09 (1.06-1.12) 1.09 (1.05-1.13) 1.22 (1.13-1.32) 1.18 (1.09-1.27)

21 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 References 4 5 1. Levine GN, Allen K, Braun LT, et al. Pet ownership and cardiovascular risk: a scientific statement 6 from the American Heart Association. Circulation 2013;127(23):2353-63. doi: 7 10.1161/CIR.0b013e31829201e1 [published Online First: 2013/05/11] 8 2. McNicholas J, Gilbey A, Rennie A, et al. Pet ownership and human health: a brief review of 9 evidence and issues. BMJ 2005;331(7527):1252-4. doi: 10.1136/bmj.331.7527.1252 10 [published Online First: 2005/11/26] 11 3. Mubanga M, Byberg L, Nowak C, et al. Dog ownership and the risk of cardiovascular disease and 12 death - a nationwide cohort study. Sci Rep 2017;7(1):15821. doi: 10.1038/s41598-017-16118- 13 6 [published Online First: 2017/11/19] 14 4. Yabroff KR, Troiano RP, Berrigan D. Walking the dog: is pet ownership associated with physical 15 activity in California? J Phys Act Health 2008;5(2):216-28. [published Online First: 16 2008/04/03]For peer review only 17 5. Westgarth C, Christley MR, Marvin G, et al. I Walk My Dog Because It Makes Me Happy: A 18 Qualitative Study to Understand Why Dogs Motivate Walking and Improved Health. 19 International Journal of Environmental Research and Public Health 2017;14(8) doi: 20 10.3390/ijerph14080936 21 22 6. McConnell AR, Brown CM, Shoda TM, et al. Friends with benefits: on the positive consequences of 23 pet ownership. J Pers Soc Psychol 2011;101(6):1239-52. doi: 10.1037/a0024506 [published 24 Online First: 2011/07/07] 25 7. Venkatasamy VV, Pericherla S, Manthuruthil S, et al. Effect of Physical activity on Insulin 26 Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus. Journal of Clinical and 27 Diagnostic Research : JCDR 2013;7(8):1764-66. doi: 10.7860/JCDR/2013/6518.3306 28 8. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes 29 and modification by exercise training. Comprehensive Physiology 2013;3(1):1-58. doi: 30 10.1002/cphy.c110062 [published Online First: 2013/05/31] 31 9. Mullersdorf M, Granstrom F, Sahlqvist L, et al. Aspects of health, physical/leisure activities, work

32 and socio-demographics associated with pet ownership in Sweden. Scand J Public Health http://bmjopen.bmj.com/ 33 2010;38(1):53-63. doi: 10.1177/1403494809344358 [published Online First: 2009/09/01] 34 10. Statistica. Dog or cat ownership rates in households by race/ethnicity in the United States in 35 2011. Google Scholar 2011 36 11. Wood L, Giles-Corti B, Bulsara M, et al. More Than a Furry Companion: The Ripple Effect of 37 Companion Animals on Neighborhood Interactions and Sense of Community. Society & 38 Animals 2007;15(1):43-56. doi: doi:https://doi.org/10.1163/156853007X169333 39 12. Siegel JM, Angulo FJ, Detels R, et al. AIDS diagnosis and depression in the Multicenter AIDS

40 on September 29, 2021 by guest. Protected copyright. Cohort Study: The ameliorating impact of pet ownership. AIDS Care 1999;11(2):157-70. doi: 41 42 10.1080/09540129948054 43 13. Enmarker I, Hellzen O, Ekker K, et al. Health in older cat and dog owners: The Nord-Trondelag 44 Health Study (HUNT)-3 study. Scand J Public Health 2012;40(8):718-24. doi: 45 10.1177/1403494812465031 [published Online First: 2012/12/12] 46 14. Friedmann E, Thomas SA, Son H, et al. Pet's presence and owner's blood pressures during the 47 daily lives of pet owners with pre-to mild hypertension. Anthrozoös 2013;26(4):535-50. 48 15. Hoerster KD, Mayer JA, Sallis JF, et al. Dog walking: its association with physical activity guideline 49 adherence and its correlates. Prev Med 2011;52(1):33-8. doi: 10.1016/j.ypmed.2010.10.011 50 [published Online First: 2010/11/05] 51 16. Lentino C, Visek AJ, McDonnell K, et al. Dog walking is associated with a favorable risk profile 52 independent of moderate to high volume of physical activity. J Phys Act Health 53 2012;9(3):414-20. [published Online First: 2011/09/22] 54 17. Parslow RA, Jorm AF. Pet ownership and risk factors for cardiovascular disease: another look. 55 Med J Aust 2003;179(9):466-8. [published Online First: 2003/10/30] 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 51

22 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 18. Utz RL. Walking the dog: The effect of pet ownership on human health and health behaviors. 4 Social Indicators Research 2014;116(2):327-39. 5 19. Wright JD, Kritz-Silverstein D, Morton DJ, et al. Pet ownership and blood pressure in old age. 6 Epidemiology 2007;18(5):613-8. doi: 10.1097/EDE.0b013e3181271398 [published Online 7 First: 2007/08/19] 8 20. Anderson WP, Reid CM, Jennings GL. Pet ownership and risk factors for cardiovascular disease. 9 Med J Aust 1992;157(5):298-301. [published Online First: 1992/09/07] 10 21. Leslie BE, Meek AH, Kawash GF, et al. An epidemiological investigation of pet ownership in 11 Ontario. Can Vet J 1994;35(4):218-22. [published Online First: 1994/04/01] 12 22. Flint E, Minot E, Perry P, et al. Characteristics of adult dog owners in New Zealand. New Zealand 13 veterinary journal 2010;58(2):69-73. 14 23. Murray JK, Browne WJ, Roberts MA, et al. Number and ownership profiles of cats and dogs in the 15 UK. Vet Rec 2010;166(6):163-8. doi: 10.1136/vr.b4712 [published Online First: 2010/02/09] 16 24. Downes M, CantyFor MJ, More peer SJ. Demography review of the pet dog and only cat population on the island of 17 Ireland and human factors influencing pet ownership. Prev Vet Med 2009;92(1-2):140-9. doi: 18 10.1016/j.prevetmed.2009.07.005 [published Online First: 2009/08/25] 19 25. Westgarth C, Pinchbeck GL, Bradshaw JW, et al. Factors associated with dog ownership and 20 21 contact with dogs in a UK community. BMC Vet Res 2007;3:5. doi: 10.1186/1746-6148-3-5 22 [published Online First: 2007/04/05] 23 26. D'Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary 24 care: The Framingham heart study. Circulation 2008;118(4):E86-E86. doi: 25 10.1161/Circulationaha.108.190154 26 27. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique resource for 27 clinical, epidemiological and genetic studies. J Intern Med 2002;252(3):184-205. [published 28 Online First: 2002/09/25] 29 28. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of a 30 biobank and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. doi: 31 10.1017/thg.2012.104 [published Online First: 2012/11/10]

32 29. Agria Pet Insurance Report. Downloaded from: http://bmjopen.bmj.com/ 33 https://www.agria.se/globalassets/sv/villkor/english/agria_villkor_hund_a4_aug2017_se_en 34 _170807_v1.pdf. 2017 35 30. Pickup E, German AJ, Blackwell E, et al. Variation in activity levels amongst dogs of different 36 breeds: results of a large online survey of dog owners from the UK. J Nutr Sci 2017;6:e10. doi: 37 10.1017/jns.2017.7 [published Online First: 2017/06/18] 38 31. Compare A, Zarbo C, Manzoni GM, et al. Social support, depression, and heart disease: a ten year 39 literature review. Frontiers in Psychology 2013;4:384. doi: 10.3389/fpsyg.2013.00384

23 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 Figure legends: 4 Figure 1 - Hazard ratios (HR) and 95% confidence intervals (CI) for the association of dog ownership and time 5 to initiation of medication for hypertension, dyslipidemia and type 2 diabetes. 6 7 Figure 2 - Coefficients and 95% confidence intervals for the exposure to dog ownership compared to 8 nondog ownership on SDtransformed biochemical and clinical measurements in the TwinGene. 9 10

11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 29, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 51 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 Figure 1. Hazard ratios (HR) and 95% confidence intervals (CI) for the association of dog ownership and time to initiation of medication for hypertension, dyslipidemia and type 2 diabetes stratified by age category,

40 on September 29, 2021 by guest. Protected copyright. sex and home occupancy (living alone or with someone) and adjusted for age, sex, marital status, presence 41 of children in the home, population density, area of residence, education level, region of birth, income and a 42 correction for latitude of residence. 43 44 90x90mm (300 x 300 DPI) 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 51 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 Figure 2. Coefficients and 95% confidence intervals for the exposure to dog ownership compared to non-dog ownership on SD-transformed biochemical and clinical measurements in the TwinGene.

40 on September 29, 2021 by guest. Protected copyright. 41 90x90mm (300 x 300 DPI) 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 51

1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Supplementary Appendix 7 8 Dog ownership and Cardiovascular Risk Factors by Mubanga et al. 9 10 11 12 Content 13 14 Supplementary Methods 15 Supplementary Table 1-10 16 Supplementary Figure 1- 4 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Methods 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 Data Source and Parameters 6 Sweden has a structured population registration system that has enabled the collection of individual 7 level information on the total population. By using an identity-protected unique code called the 8 personal identity number (PIN), it is possible to link Swedish residents through different national 9 registers for information such as vital status, socio-demographic data, dog ownership and health 10 11 outcomes.[1] 12 Covariates 13 14 Covariates extracted at baseline from the Register of the Total Population included sex, birth year, 15 region of birth separated into Sweden, other Nordic countries and non-Nordic countries; and the level 16 of education categorized as compulsory school (≤9 years), secondary school (10-11 years) and tertiary 17 education (≥12 years). We further included annually -updated covariates including marital status 18 categorized as single,For married/ registeredpeer partnership/ reviewcohabiting, only divorced or widowed; the presence of 19 children in the home (dichotomized as yes/no), the area of residence (Norrland, Svealand and 20 Götaland), the population density in municipality of residence (continuous variable), and annual 21 household income (birth year-standardized quintiles). A north-south gradient was adjusted for by 22 including the latitude of the municipality of residence. To avoid reverse effects of outcomes on 23 covariates, we used covariate data from the preceding year to time-update information on January 1 in 24 every year. A binary variable for home occupancy where individuals were assigned to ‘living alone’ if 25 the individual lived alone or ‘not alone’ if they were registered as living with a partner or a child. Co- 26 habiting partners with no children in common could not be accounted for via the registers. Another 27 variable for living with children aged <18 was created to account for those who lived with children in 28 the home. A second stratification variable was created for age group in decades. 29 30 From the SALT study conducted in 1998-2002, we used the following self-reported variables as 31 covariates: age, sex, presence of children in the household, area of residence, population density, 32 marital status, and latitude of residence and level of education as defined in the national cohort. 33 Additionally, we adjusted for tobacco use (never, former or current user), employment status 34 (employed, retired, sick leave or unemployed), Charlson comorbidity index and disability (categorized 35 as yes /no). Additionally the socioeconomic index which ranks occupations by the average level of 36 education and job earnings of job holders was also included.[2] By using National Patient Register http://bmjopen.bmj.com/ 37 data from the TwinGene clinic visit-date to five years prior, we created a Charlson comorbidity index. 38 This is a widely used index for risk adjustment in health care research.[3, 4] 39 40 TwinGene 41 The Swedish Twin Registry is a national register started in 1958 that derives information on all twin 42 43 births occurring in Sweden from the National Board of Health and Welfare. It contains information on 44 more 190,000 Swedish twin pairs born from 1886 onwards.[5] There have been several sub-studies on September 29, 2021 by guest. Protected copyright. 45 conducted within this registry that have enabled the enhancement of the phenotypic and genetic data 46 available on each participant. For this study, we limited ourselves to two sub-studies that comprised 47 participants aged 45 to 80 years and who had consented to participate in both studies. Data between 48 the two sub-studies involved was collected a minimum of 2 and a maximum of 10 years apart 49 (Supplementary Table 1, Supplementary Figure 2). 50 The first study, the Screening Across the Lifespan Twin study (SALT) interview was conducted as a 51 sub-study of the Swedish Twin Register between 1998 and 2002 targeting all twin-pairs born in 1958 52 53 or earlier. Questionnaires were used to collect information on family status, occupation, education 54 level, anthropometric measurements, alcohol intake, tobacco use, environmental exposures and 55 irritants, medication use and health - including psychosocial /personality outcomes.[5] Information 56 was collected from 44,821 respondents. 57 The second sub-study, the TwinGene study, was nested in the previous study. Between 2004 and 58 2008 participants from SALT were invited back as part of the TwinGene Study. TwinGene was set up 59 to enable the collection of biological specimens to investigate gene-environment interactions in 60

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1 2 3 participants. 12,614 invited participants gave consent to participate. Questionnaires were mailed and 4 filled in for medication use and health outcomes. Blood was then collected for clinical biochemistry BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 from a local health facility and processed centrally.[6] We used the date of clinic visit as the date of 6 study. 7 8 Clinical information was taken during TwinGene study (2004-2008), dog ownership status on the date 9 of clinical examination, and employment, profession and type of housing was extracted from the 10 SALT questionnaire (1998-2002). All variables taken from SALT are described in Supplementary 11 Table 1. 12 13

14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Table 1. Description of variables derived from the SALT questionnaire study 4 5 6 Covariate Questionnaire Option Variable created Classification and Derivative from questionnaire 7 8 Married Married, cohabiting Single Living alone 9 Marital status What is your civil status? 10 Divorced Divorced, separated, living apart 11 Widowed Widow/ widower Living in a household 12 Type of family Yes/ No Yes /No with children <18 yearsFor peer review only 13 Primary education or less 9 years or less of education 14 Highest years of education Education level Secondary education 10 to 12 years of education 15 completed Tertiary education or more More than 12 years of education 16 http://bmjopen.bmj.com/ Employed Fully employed, part time employment, owns company, on leave from work, study 17 leave or on military service 18 Employment Employment status Retired Pensioner, prematurely retired, partly retired status 19 Retired for disability or illness Retired for injury 20 Unemployed Unemployed, housewife/man 21 Level 1 Unskilled Employees 22 Level 2 Lower skilled, non-manual workers Socioeconomic 23 Socioeconomic occupation level Level 3 Self-employed excluding independent workers 24 index Level 4 Intermediate non-manual employees on September 29, 2021 by guest. Protected copyright. 25 Level 5 Highest tier non-manual employees 26 Have you ever smoked or used Never smoked No not even tried it, yes but only tried it, smoked now and then (like at parties), 27 Tobacco Use snuff Former smoker Smoked regularly, snuffed regularly, smoke now and then (like at parties) 28 Current smoker Smoke regularly, smoke at parties, snuff now and then, snuff regularly 29 Any movement Do you have any physical Yes/no Yes/ No 30 impairment handicap 31 Do you need assistance with 32 Disability personal care/ Yes/No Yes /No 33 shopping,/cooking/mobility/ 34 Less than average Almost no exercise, light exercise, much less exercise than average, less than average 35 Exercise How much do you exercise; what Average Regular medium exercise, average amount of exercise 36 fits your annual exercise pattern More than average Hard physical exercise, more exercise than average, much more exercise than 37 normal, maximum amount of exercise 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Supplementary Table 2. Description of Breed Classification of the 331 breeds included in the study based on the Nordic Kennel Union Classification 4 5 Group Breed Groups Breed Designation 6 Number 7 Sheep dogs (Australian, Belgian, Catalan, German, Picardy, Polish, Portuguese, Pyrenean, Shetland, Old English); Shepherd dogs (Belgian, Bergamasco, 8 Sheep and cattle Croatian, Dutch, German, Majorca, Polish, Romanian, South Russian); Collie (Bearded, Border, Rough, Smooth); Bouvier des Flandres, Beauceron, 1 9 dogs Briard, Chodsky Pes, Czechoslovakian Wolfdog, Komondor, Kuvasz, Mudi, Lancashire Heeler, Schipperke, Puli, Pumi, Slovakian Chuvach, Welsh 10 Corgie, Australian kelpie, Working kelpie 11 Pincher (Affenpinscher, Austrian, Dobermann, German, Miniature); Schnauzer (Giant, Miniature); Mountain Dog (Appenzeller, Bernese, Caucasian Shepherd, Entlebuch, Great Swiss, Karst, Landseer, Newfoundland, Pyrenean, Serra da Estrela, St Bernard, Uruguayan Cimarron, Yugoslavian Shepherd); 12 Pinscher and 2 Molossian For(Aidi, Anatolian peerShepherd, Boxer, Bull Mastiff,review Broholmer, Cane Corso, onlyDogo Argentino, Danish-Swedish Farm dog, Dogo Canario, Dogue de schnauzer dogs 13 Bordeux, English Bulldog, Great Dane, Hovawart, Majorca Mastiff, Mastiff, Neapolitano Mastiff, Pyrenese Mastiff, Rafeiro of Alentejo, Spanish Water 14 Dog, Shar Pei, Tosa); Central Asia Shepherd Dog, Russian Black Terrier 15 Airedale, American Staffordshire, Australian, Bedlington, Border, Brazilian, Bull, Cairn, Cesky, Dandie Dinmont, English Toy, Fox, German Hunting,

16 3 Terriers Irish Glen of Imaal, Irish Softcoated Wheaten, Irish, Jack Russel, Kerry Blue, Lakeland, Manchester, Miniaturehttp://bmjopen.bmj.com/ Bull, Norfolk, Norwich, Parson Russell, 17 Sealyham, Australian Silky, Skye, Tenterfield, Welsh, West Highland White, Yorkshire 18 4 Dachshunds Miniature, Standard, Kaninchen 19 Alaskan Malamute, American Akita, Canaan dog, Canarian Warren, Chow Chow, Cirneco dell’Etna, East Siberian Laika, Eurasian, Finnish Lapphund, Finnish Spitz, German Spitz, Greenland dog, Hokkaido, Halleforshund, Icelandic Sheepdog, Japanese Akita, Japanese Spitz, Karelian Beardog, Keeshond, 20 Spitz and 5 Korea Jindo, Laponian Herder Pharaoh Hound, Mexican Hairless dog, Norwegian Buhund, Norwegian Lundehund, Norwegian Elkhound, Peruvian 21 primitive types Hairless dog, Ibizan Hound, Pomeranian, Russian European Laika, Samoyed, Shiba, Siberian Husky, Swedish Elkhound, Swedish Lapphund, Swedish 22 White Elkhound, Swedish Vallhund, Thai Bangkaew, Thai Ridgeback, Volpino italiano, West Siberian Laika, 23 Alpine Dachsbracke, American Foxhound, Basset Artesian Normand, Basset Bleu de Gascogne, Basset fauve de Bretagne, Basset Hound, Bavarian 24 Mountain Scent hound, Beagle, Black and Tan Coonhound, Bloodhound, Bluetick Coonhound, Bosnian Coarse on September 29, 2021 by guest. Protected copyright. -haired hound, Dalmatian, Drever, Dunker 25 Scent hounds and Hound, Fawn Brittany Griffon, Finnish Hound, Foxhound, German Hound, Grand Basset Griffon Vendeen, Grand Griffon Vendeen, Griffon Nivernais, 6 26 related dogs Halden Hound, Hamilton Hound, Hygen Hound, Istrian Short-haired hound, Otterhound, Petit Basset Griffon Vendeen, Plott, Polish hunting dog, 27 Porcelain, Posavaz Hound, Rhodesian Ridgeback, Russian Hound, Russian Spotted hound, Small Blue Gascony Hound, Spanish Hound, Schiller Hound, 28 Swiss Hound, Serbian Hound, Slovakian Hound, Småland Hound Blue Picardy Spaniel, Bracco Italiano, French Pointing, Brittany, Bohemian wire-haired, Drentse Patridge, English Setter, French Spaniel, Old Danish 29 Pointer, Gordon Setter, French wire-haired Korthals Pointing Griffon, Münsterländer, Irish Red Setter, German Short/Wire-haired pointing dog, 7 Pointing dogs 30 Portuguese Pointing dog, Pointer, Pudelpointer, Slovakian Wire-haired Pointing dog, Italian Spinone, Stabyhound, Hungarian Vizsla wire-/short-haired, 31 Weimaraner short-/long-haired 32 American Cocker Spaniel, Barbet, Chesapeake Bay Retriever, Clumber Spaniel, Cocker Spaniel, Curly Coated Retriever, English Springer Spaniel, Field 33 8 Retrievers Spaniel, Flat coated Spaniel, German Spaniel, Golden retriever, Irish Water Spaniel, Labrador Retriever, Lagotto romagnolo, Nederlandse Kooikerhondje, 34 Nova Scotia Duck Tolling Retriever, Spanish Water dog, Portuguese Water Dog, Sussex Spaniel, Welsh Springer Spaniel, Wetterhound Havanese, Bolognese, Boston Terrier, Belgian Griffon, Brussels Griffon, Cavalier King Charles Spaniel, Chihuahua, Chinese Crested, Coton de Tulear, Companion and 35 9 French Bulldog, Japanese Chin, King Charles Spaniel, Kromfohrlander, Lhasa Apso, Lowchen, Maltese, Pug, Papillon, Pekingese, Small Brabant Griffon, toy dogs 36 Phalene, Prazský krysarík, Poodle, Russian Toy, Shih Tzu, Tibetan Terrier, Tibetan Spaniel 37 Afghan Hound, Azawakh, Borzoi, Polish Greyhound, Spanish Greyhound, Irish Wolfhound, Italian Greyhound, Hungarian Greyhound, Saluki, Scottish 38 10 Sight hounds Deerhound, Sloughi, Whippet 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Supplementary Table 3. Association of dog ownership with initiation of medication for the treatment of hypertension. This compares the main analysis as 4 shown in Table 2 with a modified analysis that excludes Beta-blockers which have not been recommended first line treatment for hypertension since 2006.[7] 5 6 Cox regression models with hazard ratios (HR) and 95% confidence interval (CI) are reported. 7 § 8 N treated Time at risk Model 1* Model 2 9 10 With β-blockers 503,305 10,659,258 1.02 (1.01-1.03) 1.02 (1.01-1.03) 11 Without β-blockers 401,573 11,018,086 1.03 (1.02-1.04) 1.02 (1.01-1.03) 12 For peer review only 13 *Model 1. Age and sex adjusted 14 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region of birth, income, education level, latitude of residence. 15 16 http://bmjopen.bmj.com/ 17 18 19 Supplementary Table 4. Association of dog ownership with initiation of lipid lowering medication. This compares the main analysis as shown in Table 2 20 21 with a modified analysis that censored participants at an event of angina or heart failure. Cox regression models with hazard ratios (HR) and 95% confidence 22 interval (CI) are reported. 23 § 24 Lipid lowering N treated Time at risk Model 1* Model on September 29, 2021 by guest. Protected copyright. 2 25 medication 26 Without censoring 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) 27 28 With censoring 243,797 11,482,789 1.03 (1.02-1.04) 1.02 (1.01-1.04) 29 30 *Model 1. Age and sex adjusted § 31 Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region of birth, income, education level, latitude of residence. 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 4 5 Supplementary Table 5. Additional baseline characteristics of 10,110 Swedish adults in the Swedish Twin Register. Information is based on persons who 6 participated in the TwinGene project designed to enhance the Screening Across the Lifespan Twin (SALT) questionnaire-based sub-study in the Swedish 7 8 Twin Register with biologic specimens. Numbers and % are reported unless stated otherwise. Clinical information was taken during TwinGene study (2004- 9 2008), dog ownership status on the date of clinical examination and other non-clinical details extracted from the SALT questionnaire (1998-2002). 10 11 Non-dog Mixed pedigree dog Hunting dog 12 All Dog owners For peer reviewowners only owners owners 13 Participant characteristics n n=10,110 n=484 n=9,626 n=141 n=143 14 (100%) (5.0%) (95.0%) (1.4%)* (1.4%)* 15 Employed 6,875 (68.0) 6,541 (68.0) 334 (69.0) 97 (68.8) 93 (65.0) 16 Retired 2,066 (20.4) 1,992 (20.7) 74 (15.3) http://bmjopen.bmj.com/ 18 (12.8) 29 (20.3) Employment status 10,110 17 Sick leave or illness 875 (8.7) 818 (8.5) 57 (11.8) 18 (12.8) 16 (11.2) 18 Unemployed 294 (2.90) 275 (2.9) 19 (3.9) 8 (5.7) 5 (3.5) 19 Unskilled labor 2,458 (24.3) 2,351 (24.4) 107 (22.1) 32 (22.7) 27 (18.9)

20 Lower non-manual labor 3,373 (33.4) 3,205 (33.3) 168 (34.7) 57 (40.4) 43 (30.1) Self-employed 430 (4.3) 404 (4.2) 26 (5.4) 6 (4.3) 6 (4.2) 21 Profession† 10,110 Intermediate non-manual 2,539 (25.1) 2,411 (25.0) 128 (26.4) 32 (22.7) 46 (32.2) 22 labor 23 Higher non-manual 1,310 (13.0) 1,255 (13.0) 55 (11.4) 14 (9.9) 21 (14.7) 24 employee on September 29, 2021 by guest. Protected copyright. Independent 10,100 (99.9) 9,616 (99.9) 484 (100.0) 141 (100.0) 143 (100.0) 25 Type of housing or 10,110 Assisted living2 6 (0.1) 6 (0.1) 0 (0.0) 0 (0.0) 0 (0.0) 26 accommodation Other 4 (<0.0) 4 (<0.0) 0 (0.0) 0 (0.0) 0 (0.0) 27 Biochemical Variables 28 C-Reactive Protein 9,553 Median (IQR) 1.7 (0.8-3.4) 1.7 (0.8-3.4) 1.8 (0.8-3.2) 2.0 (0.9-3.5) 1.6 (0.7-3.1) 29 LDL-Cholesterol 9,727 Mean (SE) 3.9 (0.9) 3.9 (0.9) 3.8 (0.9) 3.8 (0.9) 3.9 (0.9) 30 HDL-Cholesterol 10,109 Mean 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 31 Triglyceride (Fasting) 9,261 Median 1.1 (0.8-1.6) 1.1 (0.8-1.6) 1.1 (0.9-1.6) 1.2 (0.9-1.6) 1.2 (0.9-1.5) 32 Glucose (Non-Diabetic) 9,256 Median 5.3 (5.0-5.7) 5.3 (5.0-5.7) 5.2 (5.0-5.7) 5.3 (5.0-5.8) 5.3 (5.0-5.7)

33 HbA1c 10,097 Mean 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.7 (0.5) 34 Body Mass Index 9,618 Mean 25.9 (4.0) 25.9 (4.0) 26.0 (4.0) 26.3 (4.4) 26.0 (3.8) 35 Waist-Hip ratio 9,937 Mean 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 36 Blood pressure measurements 37 Mean systolic BP (all participants) Mean 138.1 (19.5) 138.2 (19.5) 136.0 (19.2) 139.4 (20.3) 136.2 (18.1) 38 Mean diastolic BP (all participants) 8010 Mean 82.2 (10.5) 82.2 (10.4) 82.6 (10.9) 84.8 (11.4) 82.7 (10.4) 39 Pulse pressure (all participants) Mean 55.9 (15.4) 56.0 (15.4) 53.4 (13.6) 54.6 (13.9) 53.5 (12.5)

40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Mean systolic BP (On BP Mean 144.9 (18.8) 144.9 (18.9) 144.9 (17.3) 149.4 (14.9) 142.0 (15.8) 4 treatment) Mean diastolic BP (On BP 1,970 5 Mean 83.9 (10.7) 83.8 (10.8) 85.0 (9.2) 84.5 (8.4) 85.6 (9.3) 6 treatment) Pulse pressure (On BP treatment) Mean 61.0 (16.0) 61.1 (16.1) 60.0 (13.8) 65.0 (10.1) 56.4 (12.2) 7 Excellent 3,501 (34.9) 3,330 (34.9) 171 (35.7) 33 (23.6) 58 (40.8) 8 Good 5,330 (53.2) 5,085 (53.3) 245 (51.1) 79 (56.4) 73 (51.4) Self-reported health status 10,110 9 Average 963 (9.6) 914 (9.6) 49 (10.2) 19 (13.6) 8 (5.6) 10 Not so good 227 (2.3) 213 (2.3) 14 (2.9) 7 (5.0) 3 (2.1) 11 Blood Pressure Medication 10,110 Number on treatment (%) 2,099 (20.8) 2,010 (20.9) 89 (18.4) 31 (22.0) 22 (15.4) 12 Lipid Modifying Medication 10,110 Number on treatment (%) 918 (9.1) 880 (9.1) 38 (7.9) 14 (9.5) 13 (8.3) Diabetes Medication 10,110For Number on treatmentpeer (%) 305review (3.0) 293 (3.0) only12 (2.5) 5 (3.5) 5 (3.5) 13

14 *-Proportion of this breed of total population 15 †-Defined according to Budoki et al.[8] 16 ‡-Assisted living which includes living in http://bmjopen.bmj.com/ 17 BP- Blood Pressure 18 19 20 21 22 23

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1 2 3 Supplementary Table 6. Stepwise addition of covariates into TwinGene model. Odds ratios (OR) and confidence intervals (CI) for associations of dog 4 ownership and prevalent drug prescriptions for hypertension, dyslipidemia and type 2 diabetes (n=10,110). * 5 6 7 Prescription Medication N on treatment Model 1 Model 2 Model 3 Model 4 Model 5 Model 6 Model 7 8 9 Anti-hypertensive drugs 2,223 0.96 (0.75-1.21) 0.94 (0.74-1.20) 0.95 (0.74-1.20) 0.92 (0.72-1.18) 0.90 (0.70-1.15) 0.90 (0.71-1.15) 0.90 (0.70-1.15) 10 11 Lipid lowering drugs 963 0.92 (0.65-1.29) 0.92 (0.65-1.29) 0.92 (0.66-1.29) 0.90 (0.64-1.26) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 12 Glucose lowering drugs 318 For0.89 (0.49 peer-1.61) 0.90 (0.50 -1.63)review 0.91 (0.50-1.65) 0.90only (0.50-1.63) 0.80 (0.44-1.46) 0.80 (0.44-1.46) 0.78 (0.43-1.43) 13 14 15 *Model 1, 2 and 7 were reported in the main manuscript Table 2

16 Model 1. Adjusted for age and sex http://bmjopen.bmj.com/ 17 Model 2. Adjusted for sex, age, type of family, area of residence, population density, marital status, education level and latitude of residence Model 3. Model 2 plus professional level 18 Model 4. Model 3 plus employment status 19 Model 5. Model 4 plus Charlson comorbidity index 20 Model 6. Model 5 plus disability 21 Model 7. Full twin model - Model 6 plus tobacco use 22 23

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1 2 3 Supplementary Table 7: Association of dog ownership with initiation of medication for hypertension, dyslipidaemia and diabetes. Shown for assuming 10- 4 year life-span of dog and a sensitivity analyses at 8-year and 12-year life-span of dog. 5 6 Medication Assuming 10-year life-span of dog Assuming 8-year life-span of dog Assuming 12-year life-span of dog 7 8 Sex-age Fully-adjusted Sex-age Fully-adjusted Sex-age Fully-adjusted 9 adjusted model model adjusted model model adjusted model model 10 11 Hypertension 1.02 (1.01-1.03) 1.02 (1.01-1.03) 1.02 (1.01-1.03) 1.01 (1.00-1.02) 1.03 (1.02-1.04) 1.02 (1.01-1.03) 12 For peer review only 13 Dyslipidemia 1.03 (1.02-1.04) 1.02 (1.01-1.04) 1.02 (1.01-1.04) 1.02 (1.00-1.03) 1.03 (1.02-1.04) 1.02 (1.01-1.04) 14 15 Diabetes 0.91 (0.89-0.94) 0.98 (0.95-1.01) 0.90 (0.88-0.93) 0.97 (0.94-1.00) 0.92 (0.90-0.94) 0.99 (0.96-1.02)

16 http://bmjopen.bmj.com/ 17 §Fully-adjusted models adjusted for sex, age, type of family, area of residence, population density, marital status, education level and latitude of residence 18 19 20 21 22 23

1 2 3 Supplementary Table 8: Output from fully adjusted Cox regression models for the association of dog 4 ownership with initiation of medication for hypertension. BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5

6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 1.018 0.000 1.009 1.028 9 10 Sex 11 Male Ref 12 13 Female 0.945 0.000 0.939 0.950 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer0 .90review4 0.000 only0.895 0.912 19 20 Divorced 0.993 0.091 0.986 1.001 21 Widowed 1.064 0.000 1.053 1.076 22 23 Children in home 24 25 No Ref 26 Yes 0.922 0.000 0.915 0.930 27 28 Area of Residence 29 30 Norrland Ref 31 Svealand 0.959 0.000 0.946 0.972 32 33 Götaland 0.912 0.000 0.895 0.929 34 35 Population density 1.000 0.203 0.998 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 0.955 0.000 0.949 0.962 40 41 Tertiary level 0.832 0.000 0.826 0.839 42 43 Country of birth 44 Sweden Ref on September 29, 2021 by guest. Protected copyright. 45 46 Other Nordic countries 1.143 0.000 1.128 1.157 47 48 Non-Nordic countries 1.010 0.114 0.998 1.022 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 0.994 0.195 0.985 1.003 54 Income level 3 0.995 0.297 0.986 1.004 55 56 Income level 4 0.991 0.056 0.982 1.000 57 58 Income level 5 (highest tier) 0.986 0.004 0.977 0.995 59 Latitude of residence 1.000 0.000 1.000 1.000 60

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1 2 3 Supplementary Table 9: Output from fully adjusted Cox regression models for the association of dog 4 ownership with initiation of medication for dyslipidaemia BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5

6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 1.024 0.000 1.011 1.036 9 10 Sex 11 Male Ref 12 13 Female 0.773 0.000 0.767 0.779 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer0 .83review5 0.000 only0.825 0.846 19 20 Divorced 0.992 0.117 0.982 1.002 21 Widowed 1.022 0.004 1.007 1.038 22 23 Children in home 24 25 No Ref 26 Yes 0.891 0.000 0.881 0.901 27 28 Area of Residence 29 30 Norrland Ref 31 Svealand 1.005 0.597 0.987 1.024 32 33 Götaland 0.928 0.000 0.905 0.952 34 35 Population density 1.000 0.000 0.999 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 0.963 0.000 0.954 0.972 40 41 Tertiary level 0.796 0.000 0.787 0.804 42 43 Country of birth 44 Sweden Ref on September 29, 2021 by guest. Protected copyright. 45 46 Other Nordic countries 1.169 0.000 1.150 1.189 47 48 Non-Nordic countries 1.195 0.000 1.177 1.213 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 1.000 0.962 0.988 1.012 54 Income level 3 1.004 0.504 0.992 1.016 55 56 Income level 4 1.010 0.104 0.998 1.022 57 58 Income level 5 (highest tier) 1.005 0.450 0.992 1.018 59 Latitude of residence 1.000 0.813 1.000 1.000 60

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1 2 3 Supplementary Table 10: Output from fully adjusted Cox regression models for the association of 4 dog ownership with initiation of medication for diabetes. BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 0.982 0.193 0.954 1.009 9 10 Sex 11 Male Ref 12 13 Female 0.546 0.000 0.536 0.556 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer1.244 review 0.000 only1.215 1.274 19 20 Divorced 1.196 0.000 1.171 1.223 21 Widowed 1.290 0.000 1.248 1.334 22 23 Children in home 24 25 No Ref 26 Yes 0.965 0.002 0.944 0.988 27 28 Area of Residence 29 30 Norrland Ref 31 Svealand 0.909 0.000 0.874 0.946 32 33 Götaland 0.883 0.000 0.837 0.932 34 35 Population density 0.999 0.000 0.998 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 0.877 0.000 0.861 0.894 40 41 Tertiary level 0.635 0.000 0.620 0.650 42 43 Country of birth 44 Sweden Ref on September 29, 2021 by guest. Protected copyright. 45 46 Other Nordic countries 1.116 0.000 1.076 1.159 47 48 Non-Nordic countries 1.952 0.000 1.900 2.004 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 0.919 0.000 0.896 0.941 54 Income level 3 0.845 0.000 0.824 0.866 55 56 Income level 4 0.777 0.000 0.757 0.797 57 58 Income level 5 (highest tier) 0.702 0.000 0.683 0.722 59 Latitude of residence 1.000 0.001 1.000 1.000 60

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1 2 3 Supplementary Figure 1: Study population 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 7 8 3,412,946 Swedish residents aged between 45 9 and 80 years on October 1st 2006 10 11 12 13 14 15 12,105 individuals from 11,298 individuals with unverified 16 the TwinGene cohort aged or re-used identification numbers 17 47-80 years and/or incomplete education 18 For peer review only records 19

20 21 1,373 individuals had a 22 history of cardiovascular 137,306 individuals migrated to 23 disease 24 Sweden after 1991 or emigrated 25 before study start 26 27 622 with incomplete or 28 missing data 29 531,658 individuals had a history 30 of cardiovascular disease 31 32 33 705,819 individuals had a history 34 10,110 individuals (5.0%) dog owners) with baseline measurements of cardiovascular risk of using anti-hypertensive drugs, 35 36 factors lipid-modifying drugs or blood http://bmjopen.bmj.com/ 37 glucose lowering drugs 38 39 40 41 2,026,865 eligible individuals (14.6% dog 42 owners) followed up to outcome, death, 43 emigration or study end December 31st 2012 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Figure 3: Direct Acyclic Graph for dog ownership and cardiovascular risk. The highlighted variables (comorbidity, disability and body mass 4 index) were only available in the TwinGene cohort. 5 6 7 8 9 10 11 12 For peer review only 13 14 15

16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23

1 2 3 Supplementary Figure 4. Hazard ratios (HR) and 95% confidence intervals (CI) for the association 4 of dog ownership and time to initiation of medication for hypertension, dyslipidemia and type 2 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 diabetes examining associations in hunting-type breeds (combining Terriers, Scent Hounds, Pointing 7 dogs and Retrievers) and mixed pedigree dogs and adjusted for age, sex, marital status, presence of 8 children in the home, population density, area of residence, education level, region of birth, income 9 and a correction for latitude of residence. 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 References BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 1. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, et al. The Swedish personal identity number: 7 possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24(11):659- 8 67. doi: 10.1007/s10654-009-9350-y [published Online First: 2009/06/09] 9 10 2. Ganzeboom HB, De Graaf PM, Treiman DJ. A standard international socio-economic index of 11 occupational status. Social science research 1992;21(1):1-56. 12 3. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in 13 longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-83. [published 14 Online First: 1987/01/01] 15 4. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score 16 for risk adjustment in hospital discharge abstracts using data from 6 countries. American 17 journal of epidemiology 2011;173(6):676-82. 18 For peer review only 19 5. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique resource for 20 clinical, epidemiological and genetic studies. J Intern Med 2002;252(3):184-205. [published 21 Online First: 2002/09/25] 22 6. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of a biobank 23 and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. doi: 24 10.1017/thg.2012.104 [published Online First: 2012/11/10] 25 7. Lakemedelsverket. Prevention of atherosclerotic cardiovascular disease - Treatment 26 recommendation. https://lakemedelsverketse/upload/halso-och- 27 28 sjukvard/behandlingsrekommendationer/080313_primarpreventionpdf 2006 29 8. Bukodi E, Erikson R, Goldthorpe JH. The effects of social origins and cognitive ability on educational 30 attainment. Acta Sociologica 2014;57(4):293-310. doi: doi:10.1177/0001699314543803 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml in press. press. in Commons ( Attribution Creative under isprotected *Checklist Working RECORD SM, the von HT, Elm E, Sørensen Langan I, Petersen D, Moher K, Harron A, SmeethGuttmann L, EI, Benchimol *Reference: Statement. health (RECORD) Data Routinely-collected Observational using Conducted studies of REporting The Committee. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 51 of BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-023447.R2 review only Article Type: Research

Date Submitted by the 01-Nov-2018 Author:

Complete List of Authors: Mubanga, Mwenya; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory Byberg, Liisa; Uppsala Universitet, Department of Surgical Sciences, Orthopedics, Uppsala University Egenvall, Agneta; Swedish University of Agricultural Science, Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary Epidemiology Sundström, Johan; Uppsala University Magnusson, Patrik; Karolinska Institutet, Department of Medical Epidemiology and Biostatistics Ingelsson, Erik; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory; Stanford University Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, http://bmjopen.bmj.com/ Fall, Tove; Uppsala University, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory

Primary Subject Epidemiology Heading:

Secondary Subject Heading: Cardiovascular medicine, Diabetes and endocrinology

Cardiac Epidemiology < CARDIOLOGY, EPIDEMIOLOGY, Hypertension < on September 29, 2021 by guest. Protected copyright. Keywords: CARDIOLOGY, General diabetes < DIABETES & ENDOCRINOLOGY

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1 1 2 3 Dog ownership and Cardiovascular Risk Factors: a nationwide prospective 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 register-based cohort study 6 7 8 Mwenya Mubanga, MBChB, MPH1; Liisa Byberg, PhD2; Agneta Egenvall, VMD, PhD3; 9 10 Johan Sundström MD, PhD4, Patrik K Magnusson, PhD5; Erik Ingelsson, MD, PhD1,6,7; Tove 11 12 1* 13 Fall, VMD, PhD 14 15 16 1. Department of Medical Sciences, Molecular Epidemiology and Science for Life 17 18 Laboratory, ForUppsala University,peer Uppsala,review Sweden. only 19 20 2. Department of Surgical Sciences, Orthopedics, Uppsala University, Uppsala, Sweden. 21 22 23 3. Department of Clinical Sciences, Division of Ruminant Medicine and Veterinary 24 25 Epidemiology, Swedish University of Agricultural Sciences, Uppsala, Sweden. 26 27 4. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 28 29 30 Uppsala. Sweden. 31 32 5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 33 34 Stockholm, Sweden. 35 36 6. Department of Medicine, Division of Cardiovascular Medicine, Stanford University http://bmjopen.bmj.com/ 37 38 39 School of Medicine, Stanford, CA, USA. 40 41 7. Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA. 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 *Corresponding author: Tove Fall, VMD, PhD, [email protected] 48 49 50 51 52 53 54 55 56 57 58 59 60

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2 1 2 3 Abstract 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Objective: To study the association between dog ownership and cardiovascular risk factors. 7 8 Design: A nationwide register–based cohort study and a cross-sectional study in a subset. 9 10 Setting: A cohort of 2,026,865 participants was identified from the Register of the Total 11 12 Population and linked to national registers for information on dog ownership, hospital 13 14 admissions, education level, income and country of birth. Participants were followed from 15 October 1st, 2006, to the end of the study on December 31st, 2012, assessing medication for a 16 17 cardiovascular risk factor, emigration and death. Cross-sectional associations were further 18 For peer review only 19 assessed in 10,110 individuals from the TwinGene study with additional adjustment for 20 21 professional level, employment status, Charlson comorbidity index, disability and tobacco 22 use. 23 24 25 Participants: All Swedish residents aged 45-80 years on October 1st, 2006. 26 27 Main outcome measures: Initiation of medication for hypertension, dyslipidemia and 28 diabetes mellitus. 29 30 31 Results: After adjustment for confounders, the results indicated slightly higher likelihood of 32 initiating anti-hypertensive (HR, 1.02; 95% CI, 1.01-1.03) and lipid-lowering treatment (HR, 33 34 1.02; 95% CI, 1.01-1.04) in dog owners than in non-owners, particularly amongst those aged 35 36 45 to 60 and in those owning mixed breed or companion/toy breed dogs. No association of http://bmjopen.bmj.com/ 37 38 dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 39 0.98; 95% CI, 0.95-1.01). Sensitivity analyses in the TwinGene cohort indicated confounding 40 41 of the association between dog ownership and prevalent treatment for hypertension, 42 43 dyslipidemia and diabetes mellitus, respectively from factors not available in the national 44 cohort, such as employment status and non-CVD chronic disease status. on September 29, 2021 by guest. Protected copyright. 45 46 47 Conclusions: In this large cohort study, dog ownership was associated with a minimally 48 higher risk of initiation of treatment for hypertension and dyslipidemia implying that the 49 50 previously reported lower risk of cardiovascular mortality among dog owners in this cohort is 51 52 not explained by reduced hypertension and dyslipidemia. These observations may suffer from 53 54 residual confounding despite access to multiple important covariates, and future studies may 55 add valuable information. 56 57 58 59 60

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3 1 2 3 Strengths and limitations of this study 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5  This is the largest study to date to examine the impact of dog ownership on 6 7 cardiovascular risk factors. 8  The nationwide register-based cohort study with a cross-sectional investigation in a 9 twin registry with a vast array of lifestyle and clinical variables strengthens the results. 10 11  The main outcome measures were extracted from nationwide registers thus decreasing 12 the risk of recall and selection bias. 13 14  Misclassification of dog ownership, particularly in the twin register, may have led to 15 some loss of power. 16  Some important confounding factors were not available in the national data. 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4 1 2 3 Introduction 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 There is a growing interest in pet ownership as a possible intervention to enhance 7 cardiovascular health and well-being.[1, 2] We recently observed that being registered as a 8 9 dog owner was associated with a lower risk of cardiovascular and all-cause mortality in the 10 11 general Swedish population (n=3,432,153).[3] Any causal association of dog ownership with 12 13 lower cardiovascular mortality could potentially be mediated through increased physical 14 activity[4, 5] or through the psychological benefits of companionship,[6] which could in turn 15 16 reduce other important cardiovascular risk factors such as blood pressure, adiposity, 17 18 dyslipidemia, and insulinFor resistance.[7, peer 8] review An alternative explanation only could be confounding by 19 20 socioeconomic,[9] cultural,[10] demographic[9] or psycho-social factors.[11, 12] A large 21 number of cross-sectional and longitudinal studies across different countries support the 22 23 association of dog ownership with physical activity,[1] however, reports regarding the 24 25 association of dog ownership with other cardiovascular risk factors are less consistent.[13-20] 26 These inconsistences may be due to low statistical power in small studies, use of restricted or 27 28 homogenous populations, inability to control for differences across breeds of dogs, or simply 29 30 an absence of effect. As dogs are reported to be more common in rural areas compared to 31 32 urban areas,[21-23] as well as in households with children,[24, 25] it is also important to 33 account for these differences. The aim of this study was to assess the association of dog 34 35 ownership with three major clinical risk factors for cardiovascular disease,[26] specifically 36 http://bmjopen.bmj.com/ 37 initiation of treatment of hypertension, dyslipidemia and diabetes mellitus. We hypothesized 38 39 that the cardiovascular risk profile of dog owners is better than that of non-dog owners. To 40 overcome limitations of previous studies concerning study size, generalizability and 41 42 differences between dog breeds, we investigated this hypothesis using data on all Swedish 43 44 residents aged 45-80 years of age in 2006 from national registers on dog ownership and drug on September 29, 2021 by guest. Protected copyright. 45 prescriptions. We further sought to explore the association with other cardiovascular risk 46 47 factors using cross-sectional data from a sub-cohort extracted from the Swedish Twin 48 49 Registry containing detailed information from questionnaire data, physical examinations and 50 51 laboratory measurements. 52 53 54 55 56 57 58 59 60

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5 1 2 3 Methods 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Design 7 8 The main analysis was based on a nationwide cohort study of Swedish residents aged 45-80 9 10 followed from October 1st 2006, to December 31st 2012. We additionally used cross- 11 12 sectional data of participants (aged 47-80) in the TwinGene study, which is a sub-study of the 13 Swedish Twin Registry (Supplementary Figure 1). 14 15 16 Study Population – National Cohort 17 18 For peer review only

19 All Swedish residents (n=3,412,946) aged 45-80 on October 1st 2006, were identified through 20 the Register of the Total Population. To ensure complete linkage to medical information and 21 22 sufficient information regarding dog ownership in Sweden, we excluded 11,298 individuals 23 24 with unverified, re-used identification numbers or missing education information, and 25 26 137,306 additional individuals that had resided in Sweden for <15 years. We also excluded 27 531,658 individuals with a history of any CVD (International Classification of Disease (ICD)- 28 29 9 codes 390-459 and ICD-10 I00-I99) before October 1st, 2006 or with a history of coronary 30 31 artery bypass grafts or percutaneous coronary artery intervention medical procedure (Nordic 32 33 surgical procedure codes FNA, FNC and FNG) from in- and outpatient data. Inpatient data 34 was available from 1987 and outpatient data from 2001. Further, using data from the Swedish 35 36 Prescribed Drug Register, which covers all Swedish dispensed pharmacy prescriptions since it http://bmjopen.bmj.com/ 37 38 was established on July 1st 2005, individuals (n=705,819) were excluded if they had any 39 recorded dispensed prescription of anti-hypertensive drugs, lipid-lowering drugs, or glucose 40 41 lowering drugs from 15 months prior to baseline (which was when this register was initiated). 42 43 Anti-hypertensive drugs were defined based on the Anatomical Therapeutic Chemical 44 on September 29, 2021 by guest. Protected copyright. 45 Classification System (ATC) as codes: C02 (antihypertensive drugs), C03A, C03EA01 46 (thiazide diuretics), C07 (beta-receptor blockers, excluding sotalol [C07AA07]), C08C 47 48 (selective calcium antagonists with mainly vascular effects) and C09 (agents acting on the 49 50 renin-angiotensin system). Lipid-lowering drugs were defined as C10AA (statins), C10AB 51 52 (fibrates), C10AC (bile acid sequestrants), C10AX (other lipid-modifying agents) and C10B 53 (lipid-lowering drug combinations). Glucose-lowering drugs were defined as ATC-code 54 55 A10A (insulin and analogues) and A10B (glucose-lowering drugs excluding insulin). 56 57 58 59 60

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6 1 2 3 Study population – TwinGene 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 The TwinGene study originally included 12,614 (of 22,391 invited) twins from the 7 “Screening Across the Lifespan Twin study” (SALT). It was conducted between April 2004 8 9 and December 2008 and included a visit to the participants’ local health center and blood 10 11 sampling (Supplementary Figure 2).[27] The study-base “SALT” was a sub-study of the 12 13 Swedish Twin Register in twins born before 1959 and who participated in a telephone-based 14 questionnaire sub-study from March 1998 to March 2002[27] (Supplementary Table 1). 15 16 17 We performed a cross-sectional analysis of the association of dog ownership with 18 For peer review only 19 cardiovascular risk factors in the TwinGene cohort (n=12,105). We excluded 1,373 20 individuals for having a previous history of CVD recorded in the National Patient 21 22 Register.[28] We also excluded 622 individuals for having missing or incomplete data 23 24 (Supplementary Figure 1). 25 26 Exposure 27 28 29 Dogs in Sweden are required to have a unique identifier (ear tattoo or implanted identity chip) 30 31 and this is registered alongside their owner’s unique personal identity number at the Swedish 32 Board of Agriculture. All dogs sold as purebred are registered by the Swedish Kennel Club. 33 34 In Sweden, there are virtually no stray dogs,[29] and compliance to regulations is thought to 35 36 be high due to a general high level of social and institutional trust.[30] http://bmjopen.bmj.com/ 37 38 We defined the variable ‘dog ownership’ in the national cohort as registered dog ownership or 39 40 having a partner registered as a dog owner in either the Swedish Board of Agriculture and/or 41 42 the Swedish Kennel Club registers. Exposure to dog ownership was time-updated to include 43 44 only those periods where each dog was alive and registered to the study participant or their on September 29, 2021 by guest. Protected copyright. 45 registered partner. The identification of partners was possible through annual extracts from 46 47 the Register of the Total Population that keeps track of couples that are married, registered in 48 49 same-sex partnership or are cohabiting with common children. It is presently not possible to 50 identify cohabiting non-married partners who have no children in common in the population 51 52 registers. 53 54 55 In the TwinGene data, we did not have access to information on partners’ dog ownership and 56 only each person’s own dog registrations were used. Dog ownership was defined at the date 57 58 of inclusion in TwinGene. 59 60

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7 1 2 3 If information on a dog’s death was missing, we assumed a maximum lifespan of ten 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 years.[31] We conducted sensitivity analyses examining associations with dog death at a 6 7 maximum lifespan of 8 years and 12 years. Where birth or registration dates were discrepant 8 between the two registers, we randomly selected one of the two. 9 10 11 To define breed groups, we used the Federation Cynologique International standard with 12 13 some local adaption from Swedish Kennel Club’s definition to categorize the 331 breeds into 14 ten breed groups based on character and behaviour attributes (Supplementary Table 2). All 15 16 non-purebred dogs and those of unknown breed were included in an additional mixed breed 17 18 group. Where ownersFor had dogs peer of different review breeds, we defined only the breed based on the dog 19 20 registered first and where owners had several dogs, we restricted ownership to three dogs. 21 22 Based on previous findings [3] that ownership to four different breed groups was associated 23 24 with a lower risk of cardiovascular events, we defined a group of these dog breeds (Terriers, 25 26 Pointing, Scent Hounds and Retrievers) for additional exploratory analysis. This group is 27 hereafter referred to as ‘active dog breeds’ as these breeds also generally demand high levels 28 29 of physical activity. 30 31 32 Outcome 33 34 In the national cohort, time to first dispensed prescription of anti-hypertensive drugs, lipid- 35 36 lowering drugs or glucose-lowering drugs after baseline was defined from data extracted from http://bmjopen.bmj.com/ 37 38 the drug register. Each outcome was considered separately as we chose to estimate the total 39 effect of dog ownership and not only the direct effects. Participants were censored at 40 41 emigration, death or at the end of the study on December 31st, 2012. In the analysis of time to 42 43 anti-hypertensive medication, individuals were additionally censored at a diagnosis of heart 44 failure, unstable angina or acute myocardial infarction in the National Patient Register as the on September 29, 2021 by guest. Protected copyright. 45 46 same drugs could be administered for their treatment. 47 48 49 Prevalent use of anti-hypertensive, lipid-lowering or glucose-lowering drugs was defined 50 from the clinical questionnaire data collected during the TwinGene study. Cardiovascular risk 51 52 factors measured and also used as outcomes in TwinGene included blood glucose, 53 54 glycosylated hemoglobin A1c (HbA1c), high sensitive C-reactive protein (hsCRP), 55 56 triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein- 57 cholesterol (LDL-C), waist-hip ratio, body mass index (BMI), systolic and diastolic blood 58 59 pressure and mean arterial pressure (MAP) (Supplementary methods). Only fasting 60

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8 1 2 3 measurements of glucose and triglycerides were used (9,873 [97%] of all participants were 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 fasting). 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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9 1 2 3 Statistical analyses 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 All statistical analyses were conducted using Stata version MP14.1 (StataCorp). 7 8 Using age as a time-scale, separate multivariable Cox proportional hazards models were 9 10 applied to assess the associations between dog ownership and time to initiation of anti- 11 12 hypertensive, lipid-lowering and glucose-lowering drugs, respectively. Directed acyclic 13 graphs were used to guide the choice of covariates (Supplementary Figure 3). A first crude 14 15 model included age and sex, and a second model additionally included the region of birth, 16 17 area of residence, latitude of residence, population density, level of education, marital status, 18 For peer review only 19 presence of children in the home and income. A description of the covariates is provided in 20 the Supplementary methods. The proportional hazards assumption was verified by plotting 21 22 Schoenfield residuals and log-log graphs. Results were reported as hazard ratios (HR) and 23 24 95% confidence intervals (CI). We repeated the calculations using the breed group as 25 26 exposure to examine possible breed group effects and we applied Bonferroni correction (for 27 11 breed groups) to control for multiple testing. Further analyses were stratified by age group, 28 29 sex, and whether participants lived alone or not. Individuals considered as “living alone” did 30 31 not have any spouse, partner with common children, or children living in the same household. 32 33 We conducted a sensitivity analysis where we excluded β-blockers as first line anti- 34 35 hypertensive treatment to estimate the effect of changing treatment guidelines over the study 36 http://bmjopen.bmj.com/ 37 period. In additional sensitivity analysis, in the lipid-lowering medication analysis, we 38 assessed the effect of censoring participants at a diagnosis of heart failure, unstable angina or 39 40 acute myocardial infarction in the National Patient Register. 41 42 43 Logistic regression was applied in TwinGene for the association of dog ownership with 44 prevalent anti-hypertensive, lipid-lowering and blood-glucose lowering medication and linear on September 29, 2021 by guest. Protected copyright. 45 46 regression for the association of dog ownership with continuous variables. hsCRP and 47 48 triglycerides were transformed to the natural log scale before analysis to approach normality. 49 50 In addition to adjusting for age, sex, presence of children in the household, area of residence, 51 population density, marital status, latitude of residence and level of education, we added 52 53 further covariates, one at a time to investigate their individual importance: tobacco use, 54 55 occupational level, employment status, Charlson comorbidity index and disability. In all twin 56 57 analyses, standard errors were adjusted with the robust sandwich estimator for dependent 58 observations. For blood pressure and lipid levels, associations were further stratified by 59 60 current medication.

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10 1 2 3 Ethical approval 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 The regional ethical review board in Stockholm, Sweden, approved the study (national study: 7 2012/1114-31/2, with amendment 2013-1687-32; TwinGene: 2007/644-31/2 and 2016/1392- 8 9 31/1). 10 11 12 Patient involvement 13 14 No patients were involved in the development, design or analysis of this study. The review 15 16 board allowed the researchers to waive the requirement for obtaining informed consent in the 17 18 national study. ParticipantsFor inpeer TwinGene reviewprovided written informedonly consent. 19 20 Results 21 22 23 National Cohort 24 25 The baseline characteristics of 2,026,865 Swedish residents are shown in Table 1. Dog 26 27 ownership was directly registered in 189,355 (9.3%) at any time during the follow-up period, 28 29 and this increased to 295,682 (14.6%) individuals when partners’ registration were included. 30 At baseline, the average age of dog owners was 50 years vs 53 years in non-owners. Dog 31 32 owners were more likely to be married than non-owners (78% vs 60%) and more likely to live 33 34 in low-density areas than non-owners (median: 49 vs 77 inhabitants per square kilometer). 35 Compared to non-owners, mixed pedigree dog owners (n=32,003) were less likely to be 36 http://bmjopen.bmj.com/ 37 married (59 %), were less likely to have a tertiary education (21%) and had fewer people in 38 39 the top quintile for income (12.2%). Owners of ‘active dog breeds’ showed similar 40 41 characteristics to the overall dog owners. 42 43 Medication for cardiovascular risk factors 44 on September 29, 2021 by guest. Protected copyright. 45 During 10,692,258 person-years of follow-up, dog ownership was associated with a 2% 46 47 higher risk of initiation of anti-hypertensive drug medication in both crude and multivariable- 48 49 adjusted analyses (HR, 1.02; 95% CI, 1.01-1.03). During 11,508,349 person-years of follow- 50 51 up, there was a 2% higher risk of initiating lipid-lowering medication in the multivariable 52 adjusted models (HR, 1.02; 95% CI, 1.01-1.04). During 12,207,964 person-years of follow- 53 54 up, there was a lower risk of initiating glucose lowering drugs in dog owners in minimally 55 56 adjusted models (HR, 0.91; 95% CI, 0.89-0.94), but on multivariable adjustment, the 57 association was attenuated and non-significant (HR, 0.98; 95% CI, 0.95-1.01) (Table 2). 58 59 60

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11 1 2 3 Owners of “Companion/toy” breeds and of dogs of mixed pedigree were at higher risk of anti- 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 hypertensive and lipid-lowering drug initiation compared to non-dog owners (Table 3). 6 7 Owners of the Spitz/primitive breed types and the combined group of ‘active dog breeds’ 8 breed-types had lower risks of initiating glucose-lowering medication (HR, 0.83; 95% CI, 9 10 0.74-0.93 and HR, 0.92; 95% CI, 0.86-0.97 respectively), while owners of mixed pedigree 11 12 dogs had higher risk of getting glucose-lowering medication (HR, 1.17; 95% CI, 1.09-1.26) 13 14 (Supplementary Figure 4). 15 16 There was no difference in strength of association when we excluded β-blockers as first-line 17 treatment for anti-hypertension (Supplementary Table 3) or when censoring was done in 18 For peer review only 19 those being investigated for lipid-lowering treatment initiation was made for angina, 20 21 myocardial infarction or heart failure was conducted (Supplementary Table 4). 22 23 In age-stratified analysis, there were some evidence of effect modification by age for both 24 25 anti-hypertensive and lipid-lowering drugs where an increased risk was observed in those 26 27 aged below 50 years (HR, 1.04; 95% CI, 1.01-1.08 and HR, 1.10; 95% CI, 1.04-1.15, 28 respectively), with estimates gradually approaching one with increasing age (Figure 1). 29 30 Inverse associations of dog ownership with glucose-lowering drugs was observed in the lower 31 32 age groups, in males and those not living alone (HR, 0.89; 95% CI, 0.79-0.99, HR, 0.95; 95% 33 34 CI, 0.92-0.99 and HR, 0.91; 95% CI, 0.86-0.97, respectively). 35 36 TwinGene http://bmjopen.bmj.com/ 37 38 On cross-sectional analysis of 10,110 individuals, 484 (5%) were registered as dog owners 39 40 (partners’ dogs not included) and their characteristics are described in Table 1 and 41 Supplementary Table 5. Using similar covariates as in the national cohort, no association of 42 43 dog ownership was found with prevalent use of anti-hypertensive drugs (OR, 0.94; 95% CI, 44 on September 29, 2021 by guest. Protected copyright. 45 0.74-1.20), lipid-lowering drugs (OR, 0.92; 95% CI, 0.65-1.29) or glucose-lowering drugs 46 47 (OR, 0.90; 95% CI, 0.50-1.63) (Table 2). Upon inclusion of additional covariates, the 48 Charlson comorbidity index and the employment status were found to be the most influential 49 50 confounders and the fully adjusted model yielded lower but still non-significant estimates: 51 52 OR, 0.90 (95% CI, 0.70-1.15) for use of anti-hypertensive drugs, OR, 0.87 (95% CI, 0.62- 53 1.22) for lipid-lowering drugs and OR, 0.78 (95% CI, 0.43-1.43) for glucose-lowering drugs 54 55 (Supplementary Table 6). We found no association between dog ownership and the other 56 57 clinical and biochemical cardiovascular risk factors (Figure 2). 58 59 60

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12 1 2 3 Sensitivity analyses on changing the maximum lifespan of dogs in the national cohort that had 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 no dates of death to 8 years or 12 years yielded similar results to the maximum of 10 years 6 7 used in the main analysis (Supplementary Table 7). To provide additional information, the 8 output from the fully adjusted Cox regression models for the association of dog ownership 9 10 with the initiation of medication for hypertension, dyslipidemia and diabetes mellitus in the 11 12 national cohort are included in the supplementary material as Supplementary Table 8, 13 14 Supplementary Table 9 and Supplementary Table 10, respectively. 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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13 1 2 3 Discussion 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 In this nationwide study in a population without previous cardiovascular disease, we observed 7 a minimally higher risk of initiation of treatment for hypertension and dyslipidemia among 8 9 persons with a dog in their household compared to those without dogs in the household. 10 11 Associations were most prominent in younger age groups (45-60 years). Owning a dog of 12 13 mixed pedigree or a dog belonging to the “companion/toy” breed group was associated with 14 hypertension and dyslipidemia, whilst ownership of a dog from the “Spitz/primitive” breed 15 16 and the combined group of ’active dog breeds’, consisting of breeds identified in our previous 17 18 study (Terriers, Pointing,For Scent peer Hounds andreview Retrievers),[3] only was associated with lower risk of 19 20 treatment for diabetes mellitus. Cross-sectional analyses in 10,110 participants from 21 TwinGene showed no association of dog ownership with body mass index, waist-to-hip-ratio, 22 23 blood pressure or biochemical cardiovascular risk factors, and indicated that the association of 24 25 dog ownership with medication for hypertension, dyslipidemia and diabetes was confounded 26 by employment status and non-CVD-chronic conditions. This suggests that the slightly higher 27 28 associations observed in the national cohort would potentially be attenuated in the presence of 29 30 the additional confounders. 31 32 That owners of mixed-breed and “companion/toy” breeds, as well as dog owners in younger 33 34 age groups, had mildly increased risks for hypertension and dyslipidemia are in line with our 35 36 previous study regarding higher risk of myocardial infarction and stroke in this group.[3] The http://bmjopen.bmj.com/ 37 38 level of dog walking might be lower in the smaller companion/toy dogs and mixed breed dogs 39 as compared to the ‘active dog breeds’ group, which consists of dog breeds originally bred for 40 41 hunting.[32] This was also supported by data from TwinGene where 69.9% of active dog 42 43 breeds’ breed owners reported a high level of physical activity versus 52.3% in non-dog 44 on September 29, 2021 by guest. Protected copyright. 45 owners and 58.6% for mixed-breed dog-owners.[32] We chose to analyze these four ‘active 46 dog breeds’ together (Terriers, Pointing, Scent Hounds and Retrievers) to explore the 47 48 association with CVD risk factors as they were all associated with lower risk of incident CVD 49 50 events in our previous study [3], but should not be viewed as the only active breed groups in 51 the study. We also note that the proportion of highest education level in the mixed breed 52 53 group was remarkably lower than the general population (20.9% vs 29.3%). Although we 54 55 adjusted for educational level, it is likely that there is unmeasured confounding from 56 57 differences in health-seeking behavior, smoking habits or stress in dog-owners in working age 58 groups. In TwinGene, we noted that additional adjustment for employment status 59 60 (unemployed, retired, sick leave or unemployed) and a comorbidity index (for diseases other

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14 1 2 3 than CVD) were important confounders lowering the estimates. These covariates were not 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 available in the national cohort, implying that the results in the national cohort are likely to 6 7 have been confounded by these or other factors. 8 9 Our findings in TwinGene are different from an Australian cohort study in 5,741 individuals 10 11 with 13.6% pet ownership who found lower levels of plasma cholesterol, triglycerides and 12 13 systolic blood pressures in pet-owners than non-owners.[20] Dog owners (6.3%) had better 14 self-rated health but no difference in blood pressure than non-pet owners in cross-sectional 15 16 analysis of the Nord-Trondelag Health Study (HUNT)-3 study (n=12,297).[13] 17 18 For peer review only 19 There are a limited number of studies of the association between dog ownership and the risk 20 of type 2 diabetes. A study by Lentino et al., (n=916) showed that regular dog walkers 21 22 (n=399, 44%) in a primarily well-educated Caucasian population had lower BMI and were at 23 24 lower risk of both dyslipidemia and type 2 diabetes than other study participants.[16] These 25 26 findings were contradicted by Wright et al, who showed that dog owners were more likely to 27 be overweight, and have diabetes than non-owners in a study of 1179 community dwellers 28 29 with 30% pet ownership.[19] Differences in findings across countries could be due to 30 31 differences in study design, or to inherent differences in dog management and the type of dog 32 breeds in the country. 33 34 35 A previous study in this population showed a lower risk of cardiovascular disease and all- 36 http://bmjopen.bmj.com/ 37 cause mortality in dog owners.[3] The current study suggests that it is unlikely that 38 hypertension and dyslipidemia mediates these effects. Other potential factors that may explain 39 40 this reduction in mortality include increased social well-being and decreased psychological 41 42 stress.[33] 43 44 Strengths and weaknesses on September 29, 2021 by guest. Protected copyright. 45 46 47 The main strengths of our study include its size and the population-based approach increasing 48 49 generalizability beyond healthy volunteers in a cohort study. To the best of our knowledge, 50 this is the largest register-based study to date to explore the association between dog 51 52 ownership and cardiovascular risk factors. At the same time, while national registers allow for 53 54 large and unselected populations with no loss to follow-up, they lack information on 55 56 individual attributes such as body mass index, blood pressure, lipid levels and physical 57 activity. A strength of this study is that we were able to include additional clinical health 58 59 measurements and socioeconomic variables using data from the TwinGene study supporting 60

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15 1 2 3 the presence of additional confounding of the relationship between dog ownership and 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 cardiovascular risk factors from employment status and non-CVD comorbidities. Although 6 7 our findings show an association between certain dog breeds and cardiovascular risk factors, 8 these observational results do not imply a causal relationship. 9 10 11 The main limitation of the study is the possibility of remaining unmeasured confounding by 12 13 unmeasured socioeconomic factors or pre-existing personality traits. Further, the register- 14 based nature of our study made it impossible for us to account for pet-associated factors such 15 16 as primary pet responsibility, physical activity, the level of dog attachment or indeed the 17 18 reason for acquiringFor a dog. Physical peer activity review related to dog onlywalking may however be a 19 20 mediator of the association between dog ownership and health outcomes and separating 21 activity performed in relation to dog walking and other types of activity would be important. 22 23 However, a large randomized study of dog ownership over several years cannot be done. 24 25 Further, despite adjustment for several health, socioeconomic and lifestyle indicators, there is 26 still a possibility of residual confounding or reverse causation. For instance, we could not 27 28 assess health status before pet acquisition in the national cohort. A smaller study population, 29 30 although not selected in relation to exposure or outcome, and possible misclassification of dog 31 32 ownership (due to a lack of information on partners’ dog ownership) or lifestyle questionnaire 33 data (collected some years earlier) were important limitations in the sub-cohort analyses. 34 35 Misclassification of dog ownership was also possible in non-married cohabiting partners 36 http://bmjopen.bmj.com/ 37 without children in common as these would not be registered as cohabiting in the Register of 38 39 The Total Population. Another important limitation is that we were unable to account for 40 those that did not initiate treatment due to any of the three conditions. The Prescribed Drug 41 42 Register does not keep a record of adherence to treatment or records of those prescribed 43 44 lifestyle interventions such as diet or exercise. on September 29, 2021 by guest. Protected copyright. 45 46 Conclusion 47 48 49 In this large cohort study, we observed that dog ownership was associated with a minimally 50 51 higher risk of initiation of treatment for hypertension and dyslipidemia, and that ownership of 52 dogs of the previously identified ‘active dog breeds’ was associated with a lower risk of 53 54 initiating treatment for diabetes. These observations may suffer from residual confounding 55 56 despite access to multiple important covariates, and future studies may add valuable 57 information. The observed inverse association of dog ownership and cardiovascular disease 58 59 60

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16 1 2 3 previously reported in this population are unlikely to be explained by reduced hypertension and 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 dyslipidemia. 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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17 1 2 3 Acknowledgements 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 The results of this study were previously presented as a poster at the World Congress or 6 7 Cardiology and Cardiovascular Health 2018 and an abstract was published in Global Heart 8 9 Volume 13, Issue 4, December 2018, Page 483. 10 11 We acknowledge The Swedish Twin Registry for access to data. We would also like to 12 13 acknowledge the Swedish Kennel Club and the National Board of Agriculture for granting 14 15 access to the dog registers. They were not involved in any part of the study design, analysis, 16 data interpretation, manuscript preparation or approval. Support by BILS (Bioinformatics 17 18 Infrastructure for LifeFor Sciences) peer is gratefully review acknowledged. only There was no compensation 19 20 received for this assistance. 21 22 Funding Statement 23 24 The study was funded by the Agria Research Foundation and the Swedish Research Council 25 26 for Environment, Agricultural Sciences and Spatial Planning (FORMAS), grant number 2013- 27 28 1673. T.F has personal funding from the Goran Gustafsson foundation. The Swedish Twin 29 Registry is managed by Karolinska Institutet and receives funding through the Swedish 30 31 Research Council under the grant no 2017-00641. The funders were not involved in any part 32 33 of the study design, data collection, analysis manuscript preparation or approval. 34 35 Competing financial interests 36 http://bmjopen.bmj.com/ 37 38 E.I. is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to 39 the present project. The authors report that no other competing interests exist. 40 41 42 Contributorship Statement 43 44 T.F conceived the study and acquired funding. M.M, A.E, E.I, J.S and L.B contributed to the on September 29, 2021 by guest. Protected copyright. 45 design of the study. T.F. acquired the national data and P.M is responsible for the Swedish 46 47 Twin Registry data. M.M performed data cleaning. M.M and T.F ran statistical analyses. M.M 48 49 drafted the manuscript and all authors reviewed the manuscript. 50 51 52 Data sharing statement 53 54 55 The register data that support the findings of this study were made available by record-linkage 56 57 58 with data from Statistics Sweden, the National Board of Health and Welfare, the Swedish 59 60 Kennel Club, Swedish Board of Agriculture and the Swedish Twin Register. Restrictions

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18 1 2 3 apply to the availability of these data, which were used under license and ethical approval for 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 the current study, and so are not publicly available. Data are however available from the 7 8 authors upon reasonable request and with permission of the Regional Ethical Review Board in 9 10 Stockholm, Sweden. There is no additional data available. 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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19 1 2 3 Table 1. Baseline characteristics of Swedish adults aged 45-80 years without cardiovascular disease according to dog ownership status (national 4 5 cohort, n=2,026,865) and (TwinGene, n=10,110, responses derived from SALT study [1998-2002]). Age is given at baseline. Numbers and % of 6 the respective cohort are reported unless stated otherwise. 7 8 National Cohort TwinGene 9 Non-dog Mixed ‘Active dog Non-dog Mixed 10 Dog ‘Active dog All owners Dog owners* pedigree† breeds’ †,‡ All owners pedigree† owners* breeds’ †,‡ 11 n=2,026,865 n=1,731,183 n=295,682 n=32,003 n=65,686 n=10,110 n=9,626 n=141 n=484 n=143 12 (100%) (85.4%) (14.6%) (1.6%) (3.2%) (100%) (1.3%) For peer review only(95%) (5%) (1.4%) 13 14 Age - mean  SD 52.8 (8.7) 53.3 (8.9) 49.9 (7.3) 49.2 (7.1) 50.0 (7.3) 63.6 (7.1) 63.7 (7.1) 62.0 (6.7) 61.9 (6.3) 62.7 (6.7) 15 Male 981,094 (48.4) 839,321 (48.5) 141,773 (47.9) 11,841 (37.0) 27,961 (42.6) 4,189 (41.4) 3,986 (41.4) 203 (41.9) 60 (42.6) 64 (44.8) Marital status 16 http://bmjopen.bmj.com/ Married/ cohabiting 1,276,074 (63.0) 1,044,915 (60.4) 231,159 (78.2) 18,991 (59.3) 46,638 (71.0) 8,039 (79.5) 7,648 (79.5) 391 (80.8) 110 (78.0) 112 (78.3) 17 Never married 287,589 (14.2) 265,895 (15.4) 21,694 (7.3) 4,265 (13.3) 6,377 (9.7) 771 (7.6) 734 (7.6) 37 (7.6) 13 (9.2) 14 (9.8) 18 Divorced 352,209 (17.4) 316,728 (18.3) 35,481 (12.0) 7,522 (23.5) 10,325 (15.7) 855 (8.5) 824 (8.6) 31 (6.4) 11 (7.8) 8 (5.6) 19 Widowed 110,993 (5.5) 103,645 (6.0) 7,348 (2.5) 1,225 (3.8) 2,346 (3.6) 445 (4.4) 420 (4.4) 25 (5.2) 7 (5.0) 9 (6.3) Type of family 20 Children at home 658,355 (32.4) 521,224 (30.0) 137,131 (46.3) 14,079 (44.0) 28,785 (43.8) 1,500 (14.8) 1,397 (14.5) 103 (21.3) 31 (22.0) 27 (18.9) 21 No children at home 1,369,617 (67.6) 1,210,920 (69.9) 158,697 (53.7) 17,924 (56.0) 36,901 (56.2) 8,610 (85.2) 8,229 (85.5) 381 (78.7) 110 (78.0) 116 (81.1) 22 Education Compulsory 541,662 (26.7) 473,952 (27.4) 67,710 (22.9) 8,596 (26.9) 13,207 (20.1) 4,069 (40.2) 3,880 (40.3) 189 (39.0) 56 (39.7) 52 (36.4) 23 Secondary 891,458 (44.0) 751,156 (43.4) 140,302 (47.5) 16,729 (52.3) 29,352 (44.7) 3,107 (30.7) 2,958 (30.7) 149 (30.8) 46 (32.6) 36 (25.2) 24 University 593,745 (29.3) 506,075 (29.2) 87,670 (29.7) 6,678 (20.9) 23,127 (35.2) 2,934 (29.0) 2,788 (29.0) on September 29, 2021 by guest. Protected copyright. 146 (30.2) 39 (27.7) 55 (38.5) 25 Income quintile§ 26 1 (lowest quintile) 405,929 (20.0) 342,412 (19.8) 63,517 (21.5) 8,222 (25.7) 12,695 (19.3) - - - - - 2 405,486 (20.0) 348,254 (20.1) 57,232 (19.4) 7,472 (23.3) 12,461 (19.0) - - - - - 27 3 405,173 (20.0) 347,691 (20.1) 57,482 (19.4) 6,801 (21.3) 12,586 (19.2) - - - - - 28 4 405,175 (20.0) 346,350 (20.0) 58,825 (19.9) 5,620 (17.6) 13,364 (20.3) - - - - - 29 5 (highest quintile) 405,102 (20.0) 346,476 (20.0) 58,626 (19.8) 3,888 (12.1) 14,580 (22.2) - - - - - Country of birth 30 Sweden 1,805,438 (89.1) 1,529,664 (88.4) 275,774 (93.3) 29,168 (91.1) 62,160 (94.6) 10,110 (100) 9,626 (100) 484 (100) 141 (100) 143 (100) Other Nordic 31 92,043 (4.5) 80,740 (4.7) 11,303 (3.8) 1,650 (5.2) 2,083 (3.2) 0 0 0 0 0 32 countries** Non-Nordic 129,384 (6.4) 120,779 (7.0) 8,605 (2.9) 1,185 (3.7) 1,443 (2.2) 0 0 0 0 0 33 countries 34 Population density - median (IQR) inhabitant per square kilometer 35 72.6 (228.8) 76.7 (315.3) 49.2 (92.8) 45.0 (87.7) 56.8 (106.2) 60.7 (111.1) 60.7 (114.7) 41.8 (72.9) 40.1 (70.3) 45.9 (68.5) Region of residence 36 Norrland 269,897 (13.3) 222,443 (12.8) 47,454 (16.0) 4,791 (15.0) 9,476 (14.4) 1,621 (16.0) 1,518 (15.8) 103 (21.3) 32 (22.7) 22 (15.4) 37 Svealand 771742 (38.1) 669673 (38.7) 102,069 (34.5) 10,278 (32.1) 23,451 (35.7) 3,391 (33.5) 3,240 (33.7) 151 (31.2) 41 (29.1) 42 (29.4) 38 Götaland 985,226 (48.6) 839,067 (48.5) 146,159 (49.4) 16,934 (52.9) 32,759 (49.9) 5,098 (50.4) 4,868 (50.6) 230 (47.5) 68 (48.2) 79 (55.2) †† 39 Exercise Little or none - - - - 2,139 (21.2) 2,064 (21.5) 75 (15.5) 29 (20.7) 16 (11.2) 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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20 1 2 3 Average - - - - 2,611 (25.9) 2,508 (26.2) 103 (21.3) 29 (20.7) 27 (18.9) 4 Above average - - - - 5,319 (52.8) 5,014 (52.3) 305 (63.1) 82 (58.6) 100 (69.9) Tobacco Use†† 5 No history of 4,314 (42.7) 4,155 (43.2) 159 (32.9) 42 (29.8) 46 (32.2) - - - - 6 tobacco Previous tobacco 4,061 (40.2) 3,833 (39.8) 228 (47.1) 69 (48.9) 68 (47.6) 7 - - - - user 8 Current tobacco user - - - - 1,735 (17.2) 1,638 (17.0) 97 (20.0) 30 (21.3) 29 (20.3) 9 10 *For descriptive purposes, dog owners here are individuals who had a registered dog at any time point during the study period, and for TwinGene taken as ownership at the clinical test date. 11 †Proportion of this breed of all participants 12 ‡’Active dog breeds’ which comprises all Terriers,For Scent hounds, peer Pointing dog and Retriever review dog breed groups. only 13 §Information on income not available for the TwinGene sub-study in the Swedish Twin Register; 14 **Other Nordic countries include Norway, Denmark, Iceland, Finland, the territories of the Åland Islands and the Faroe Islands ††Information on exercise levels and tobacco use was not available from the Register of the Total Population 15

16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23

21 1 2 3 Table 2. Association of dog ownership with initiation of medication for hypertension, 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 dyslipidemia and diabetes. For national cohort (n=2,026,865), Cox regression models with 6 hazard ratios (HR) and 95% confidence interval (CI) for incident medication are applied, 7 while logistic models for prevalent use is used in TwinGene (n=10,110) and odds ratios 8 presented (OR). 9 10 11 Cohort Medication N treated Time at risk Model 1* Model 2§ Model 3† 12 13 Hypertension 503,305 10,659,258 1.02 (1.01-1.03) 1.02 (1.01-1.03) NA 14 National Dyslipidemia 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) NA 15 Diabetes 60,038 12,207,964 0.91 (0.89-0.94) 0.98 (0.95-1.01) NA 16 17 Hypertension 2,223 NA 0.96 (0.75-1.21) 0.94 (0.74-1.20) 0.90 (0.70-1.15) 18 TwinGene DyslipidemiaFor peer963 reviewNA 0.92 (0.65-1.29) only0.92 (0.65-1.29) 0.87 (0.62-1.22) 19 Diabetes 318 NA 0.89 (0.49-1.61) 0.90 (0.50-1.63) 0.78 (0.43-1.43) 20 21 22 *Model 1. Age and sex adjusted 23 24 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region 25 of birth (Sweden, Nordic, Non-Nordic), income, education level, latitude of residence. TwinGene: Adjusted for sex, age, type 26 of family, area of residence, population density, marital status, education level and latitude of residence 27 † 28 Model 3. Adjusted for sex, age, number of children in the home, area of residence, population density, marital status, 29 tobacco use, occupational level, employment status, disability and Charlson comorbidity index 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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22 1 2 3 Table 3. Association of dog ownership with initiation of medication for hypertension drugs, 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 dyslipidemia and diabetes by breed group in the National cohort with non-dog owners as the 6 reference group. Estimates that pass Bonferroni correction for 11 breed groups (p=0.05/11) are 7 marked in bold. 8 9 10 Anti-hypertensive drugs Lipid-lowering drugs Glucose -lowering drugs 11 12 * † * † * † 13 Breed Groups Crude HR Adjusted HR Crude HR Adjusted HR Crude HR Adjusted HR 14 Sheep and cattle 15 1.04 (1.01-1.07) 1.03 (1.00-1.06) 1.01 (0.97-1.06) 1.01 (0.97-1.06) 1.03 (0.95-1.13) 1.06 (0.96-1.15) 16 dogs 17 Pinscher and 1.03 (0.99-1.06) 1.03 (1.00-1.07) 1.07 (1.02-1.12) 1.07 (1.02-1.12) 0.92 (0.82-1.02) 0.98 (0.88-1.09) 18 schnauzer For peer review only 19 20 Terriers 0.98 (0.95-1.02) 0.99 (0.96-1.03) 1.01 (0.96-1.05) 1.02 (0.97-1.07) 0.84 (0.76-0.94) 0.91 (0.81-1.01) 21 22 23 Dachshunds 1.01 (0.96-1.06) 1.02 (0.97-1.07) 1.06 (0.99-1.13) 1.06 (0.99-1.13) 0.96 (0.84-1.11) 1.03 (0.89-1.18) 24 25 Spitz and primitive 1.05 (1.01-1.09) 1.00 (0.97-1.04) 1.04 (0.99-1.09) 1.01 (0.96-1.06) 0.82 (0.73-0.91) 0.83 (0.74-0.93) 26 types 27 Scent hounds and 28 1.05 (1.00-1.09) 1.03 (0.98-1.07) 1.07 (1.01-1.13) 1.05 (0.99-1.11) 0.86 (0.76-0.98) 0.88 (0.77-0.99) 29 related 30 31 Pointing dogs 0.95 (0.89-1.02) 0.95 (0.88-1.02) 0.96 (0.88-1.06) 0.97 (0.89-1.07) 0.65 (0.51-0.82) 0.73 (0.58-0.93) 32 33 Retrievers 1.00 (0.98-1.03) 1.02 (0.99-1.05) 1.00 (0.96-1.04) 1.02 (0.98-1.06) 0.87 (0.80-0.95) 0.98 (0.90-1.06) 34 35 Companion and 36 1.10 (1.06-1.13) 1.09 (1.05-1.12) 1.12 (1.08-1.17) 1.12 (1.07-1.16) 1.01 (0.92-1.12) 1.03 (0.93-1.14) Toy dogs http://bmjopen.bmj.com/ 37 38 39 Sight hounds 0.90 (0.79-1.02) 0.90 (0.79-1.02) 0.94 (0.79-1.12) 0.94 (0.79-1.12) 0.84 (0.57-1.26) 0.87 (0.59-1.30) 40 41 Mixed Pedigree‡ 1.10 (1.07-1.13) 1.07 (1.05-1.11) 1.09 (1.06-1.12) 1.09 (1.05-1.13) 1.22 (1.13-1.32) 1.18 (1.09-1.27) 42 43 *Adjusted for age and sex 44 †Adjusted for age, sex, marital status, presence of children in the home, population density, area of residence, education on September 29, 2021 by guest. Protected copyright. 45 level, region of birth, income and a correction for latitude of residence. 46 ‡Group comprising all non-pure pedigree dogs. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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23 1 2 3 References 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 1. Levine GN, Allen K, Braun LT, et al. Pet ownership and cardiovascular risk: a scientific statement 6 from the American Heart Association. Circulation 2013;127(23):2353-63. doi: 7 8 10.1161/CIR.0b013e31829201e1 [published Online First: 2013/05/11] 9 2. McNicholas J, Gilbey A, Rennie A, et al. Pet ownership and human health: a brief review of 10 evidence and issues. BMJ 2005;331(7527):1252-4. doi: 10.1136/bmj.331.7527.1252 11 [published Online First: 2005/11/26] 12 3. Mubanga M, Byberg L, Nowak C, et al. Dog ownership and the risk of cardiovascular disease and 13 death - a nationwide cohort study. Sci Rep 2017;7(1):15821. doi: 10.1038/s41598-017-16118- 14 6 [published Online First: 2017/11/19] 15 4. Yabroff KR, Troiano RP, Berrigan D. Walking the dog: is pet ownership associated with physical 16 17 activity in California? J Phys Act Health 2008;5(2):216-28. [published Online First: 18 2008/04/03] For peer review only 19 5. Westgarth C, Christley MR, Marvin G, et al. I Walk My Dog Because It Makes Me Happy: A 20 Qualitative Study to Understand Why Dogs Motivate Walking and Improved Health. 21 International Journal of Environmental Research and Public Health 2017;14(8) doi: 22 10.3390/ijerph14080936 23 6. McConnell AR, Brown CM, Shoda TM, et al. Friends with benefits: on the positive consequences of 24 pet ownership. J Pers Soc Psychol 2011;101(6):1239-52. doi: 10.1037/a0024506 [published 25 Online First: 2011/07/07] 26 27 7. Venkatasamy VV, Pericherla S, Manthuruthil S, et al. Effect of Physical activity on Insulin 28 Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus. Journal of Clinical and 29 Diagnostic Research : JCDR 2013;7(8):1764-66. doi: 10.7860/JCDR/2013/6518.3306 30 8. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes 31 and modification by exercise training. Comprehensive Physiology 2013;3(1):1-58. doi: 32 10.1002/cphy.c110062 [published Online First: 2013/05/31] 33 9. Mullersdorf M, Granstrom F, Sahlqvist L, et al. Aspects of health, physical/leisure activities, work 34 and socio-demographics associated with pet ownership in Sweden. Scand J Public Health 35 36 2010;38(1):53-63. doi: 10.1177/1403494809344358 [published Online First: 2009/09/01] http://bmjopen.bmj.com/ 37 10. Statistica. Dog or cat ownership rates in households by race/ethnicity in the United States in 38 2011. Google Scholar 2011 39 11. Wood L, Giles-Corti B, Bulsara M, et al. More Than a Furry Companion: The Ripple Effect of 40 Companion Animals on Neighborhood Interactions and Sense of Community. Society & 41 Animals 2007;15(1):43-56. doi: doi:https://doi.org/10.1163/156853007X169333 42 12. Siegel JM, Angulo FJ, Detels R, et al. AIDS diagnosis and depression in the Multicenter AIDS 43 Cohort Study: The ameliorating impact of pet ownership. AIDS Care 1999;11(2):157-70. doi: 44 10.1080/09540129948054 on September 29, 2021 by guest. Protected copyright. 45 46 13. Enmarker I, Hellzen O, Ekker K, et al. Health in older cat and dog owners: The Nord-Trondelag 47 Health Study (HUNT)-3 study. Scand J Public Health 2012;40(8):718-24. doi: 48 10.1177/1403494812465031 [published Online First: 2012/12/12] 49 14. Friedmann E, Thomas SA, Son H, et al. Pet's presence and owner's blood pressures during the 50 daily lives of pet owners with pre-to mild hypertension. Anthrozoös 2013;26(4):535-50. 51 15. Hoerster KD, Mayer JA, Sallis JF, et al. Dog walking: its association with physical activity guideline 52 adherence and its correlates. Prev Med 2011;52(1):33-8. doi: 10.1016/j.ypmed.2010.10.011 53 [published Online First: 2010/11/05] 54 55 16. Lentino C, Visek AJ, McDonnell K, et al. Dog walking is associated with a favorable risk profile 56 independent of moderate to high volume of physical activity. J Phys Act Health 57 2012;9(3):414-20. [published Online First: 2011/09/22] 58 17. Parslow RA, Jorm AF. Pet ownership and risk factors for cardiovascular disease: another look. 59 Med J Aust 2003;179(9):466-8. [published Online First: 2003/10/30] 60

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24 1 2 3 18. Utz RL. Walking the dog: The effect of pet ownership on human health and health behaviors. 4 Social Indicators Research 2014;116(2):327-39. BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 19. Wright JD, Kritz-Silverstein D, Morton DJ, et al. Pet ownership and blood pressure in old age. 6 7 Epidemiology 2007;18(5):613-8. doi: 10.1097/EDE.0b013e3181271398 [published Online 8 First: 2007/08/19] 9 20. Anderson WP, Reid CM, Jennings GL. Pet ownership and risk factors for cardiovascular disease. 10 Med J Aust 1992;157(5):298-301. [published Online First: 1992/09/07] 11 21. Leslie BE, Meek AH, Kawash GF, et al. An epidemiological investigation of pet ownership in 12 Ontario. Can Vet J 1994;35(4):218-22. [published Online First: 1994/04/01] 13 22. Flint E, Minot E, Perry P, et al. Characteristics of adult dog owners in New Zealand. New Zealand 14 veterinary journal 2010;58(2):69-73. 15 23. Murray JK, Browne WJ, Roberts MA, et al. Number and ownership profiles of cats and dogs in the 16 17 UK. Vet Rec 2010;166(6):163-8. doi: 10.1136/vr.b4712 [published Online First: 2010/02/09] 18 24. Downes M, CantyFor MJ, More peer SJ. Demography review of the pet dog onlyand cat population on the island of 19 Ireland and human factors influencing pet ownership. Prev Vet Med 2009;92(1-2):140-9. doi: 20 10.1016/j.prevetmed.2009.07.005 [published Online First: 2009/08/25] 21 25. Westgarth C, Pinchbeck GL, Bradshaw JW, et al. Factors associated with dog ownership and 22 contact with dogs in a UK community. BMC Vet Res 2007;3:5. doi: 10.1186/1746-6148-3-5 23 [published Online First: 2007/04/05] 24 26. D'Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary 25 26 care: The Framingham heart study. Circulation 2008;118(4):E86-E86. doi: 27 10.1161/Circulationaha.108.190154 28 27. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique resource for 29 clinical, epidemiological and genetic studies. J Intern Med 2002;252(3):184-205. [published 30 Online First: 2002/09/25] 31 28. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of a 32 biobank and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. doi: 33 10.1017/thg.2012.104 [published Online First: 2012/11/10] 34 35 29. Hoffmann R, Lokrantz M, Lagerkvist C-J, et al. Värdet av hundar och katter i Sverige2017. 36 30. Delhey J, Newton K. Predicting Cross-National Levels of Social Trust: Global Pattern or Nordic http://bmjopen.bmj.com/ 37 Exceptionalism? European Sociological Review 2005;21(4):311-27. doi: 10.1093/esr/jci022 38 31. Agria Pet Insurance Report. Downloaded from: 39 https://www.agria.se/globalassets/sv/villkor/english/agria_villkor_hund_a4_aug2017_se_en 40 _170807_v1.pdf. 2017 41 32. Pickup E, German AJ, Blackwell E, et al. Variation in activity levels amongst dogs of different 42 breeds: results of a large online survey of dog owners from the UK. J Nutr Sci 2017;6:e10. doi: 43 10.1017/jns.2017.7 [published Online First: 2017/06/18] 44 on September 29, 2021 by guest. Protected copyright. 45 33. Compare A, Zarbo C, Manzoni GM, et al. Social support, depression, and heart disease: a ten year 46 literature review. Frontiers in Psychology 2013;4:384. doi: 10.3389/fpsyg.2013.00384 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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25 1 2 3 Figure legends: 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 Figure 1 - Hazard ratios (HR) and 95% confidence intervals (CI) for the association of dog ownership and time 6 to initiation of medication for hypertension, dyslipidemia and type 2 diabetes. 7 8 Figure 2 - Coefficients and 95% confidence intervals for the exposure to dog ownership compared to 9 non-dog ownership on SD-transformed biochemical and clinical measurements in the TwinGene. 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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40 on September 29, 2021 by guest. Protected copyright. sex and home occupancy (living alone or with someone) and adjusted for age, sex, marital status, presence 41 of children in the home, population density, area of residence, education level, region of birth, income and a 42 correction for latitude of residence. 43 44 90x90mm (300 x 300 DPI) 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 53 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 Supplementary Appendix 7 8 Dog ownership and Cardiovascular Risk Factors by Mubanga et al. 9 10 11 12 Content 13 14 Supplementary Methods 15 Supplementary Table 1-10 16 Supplementary Figure 1- 4 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Supplementary Methods 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 Data Source and Parameters 6 Sweden has a structured population registration system that has enabled the collection of individual 7 level information on the total population. By using an identity-protected unique code called the 8 personal identity number (PIN), it is possible to link Swedish residents through different national 9 registers for information such as vital status, socio-demographic data, dog ownership and health 10 1 11 outcomes. 12 Covariates 13 14 Covariates extracted at baseline from the Register of the Total Population included sex, birth year, 15 region of birth separated into Sweden, other Nordic countries and non-Nordic countries; and the level 16 of education categorized as compulsory school (≤9 years), secondary school (10-11 years) and tertiary 17 education (≥12 years). We further included annually -updated covariates including marital status 18 categorized as single,For married/ registeredpeer partnership/ reviewcohabiting, only divorced or widowed; the presence of 19 children in the home (dichotomized as yes/no), the area of residence (Norrland, Svealand and 20 Götaland), the population density in municipality of residence (continuous variable), and annual 21 household income (birth year-standardized quintiles). A north-south gradient was adjusted for by 22 including the latitude of the municipality of residence. To avoid reverse effects of outcomes on 23 covariates, we used covariate data from the preceding year to time-update information on January 1 in 24 every year. A binary variable for home occupancy where individuals were assigned to ‘living alone’ if 25 the individual lived alone or ‘not alone’ if they were registered as living with a partner or a child. Co- 26 habiting partners with no children in common could not be accounted for via the registers. Another 27 variable for living with children aged <18 was created to account for those who lived with children in 28 the home. A second stratification variable was created for age group in decades. 29 30 From the SALT study conducted in 1998-2002, we used the following self-reported variables as 31 covariates: age, sex, presence of children in the household, area of residence, population density, 32 marital status, and latitude of residence and level of education as defined in the national cohort. 33 Additionally, we adjusted for tobacco use (never, former or current user), employment status 34 (employed, retired, sick leave or unemployed), Charlson comorbidity index and disability (categorized 35 as yes /no). Additionally the socioeconomic index which ranks occupations by the average level of 36 2 education and job earnings of job holders was also included. By using National Patient Register data http://bmjopen.bmj.com/ 37 from the TwinGene clinic visit-date to five years prior, we created a Charlson comorbidity index. This 38 is a widely used index for risk adjustment in health care research.3 4 39 40 TwinGene 41 The Swedish Twin Registry is a national register started in 1958 that derives information on all twin 42 births occurring in Sweden from the National Board of Health and Welfare. It contains information on 43 5 44 more 190,000 Swedish twin pairs born from 1886 onwards. There have been several sub-studies on September 29, 2021 by guest. Protected copyright. 45 conducted within this registry that have enabled the enhancement of the phenotypic and genetic data 46 available on each participant. For this study, we limited ourselves to two sub-studies that comprised 47 participants aged 45 to 80 years and who had consented to participate in both studies. Data between 48 the two sub-studies involved was collected a minimum of 2 and a maximum of 10 years apart 49 (Supplementary Figure 1, Supplementary Figure 5). 50 The first study, the Screening Across the Lifespan Twin study (SALT) interview was conducted as a 51 sub-study of the Swedish Twin Register between 1998 and 2002 targeting all twin-pairs born in 1958 52 53 or earlier. Questionnaires were used to collect information on family status, occupation, education 54 level, anthropometric measurements, alcohol intake, tobacco use, environmental exposures and 5 55 irritants, medication use and health - including psychosocial /personality outcomes. Information was 56 collected from 44,821 respondents. 57 The second sub-study, the TwinGene study, was nested in the previous study. Between 2004 and 58 2008 participants from SALT were invited back as part of the TwinGene Study. TwinGene was set up 59 to enable the collection of biological specimens to investigate gene-environment interactions in 60

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1 2 3 participants. 12,614 invited participants gave consent to participate. Questionnaires were mailed and 4 filled in for medication use and health outcomes. Blood was then collected for clinical biochemistry BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 from a local health facility and processed centrally.6 We used the date of clinic visit as the date of 6 study. 7 8 Clinical information was taken during TwinGene study (2004-2008), dog ownership status on the date 9 of clinical examination, and employment, profession and type of housing was extracted from the 10 SALT questionnaire (1998-2002). All variables taken from SALT are described in Supplementary 11 Table 1. 12 13

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1 2 3 Supplementary Table 1. Description of variables derived from the SALT questionnaire study 4 5 6 Covariate Questionnaire Option Variable created Classification and Derivative from questionnaire 7 8 Married Married, cohabiting Single Living alone 9 Marital status What is your civil status? 10 Divorced Divorced, separated, living apart 11 Widowed Widow/ widower Living in a household 12 Type of family Yes/ No Yes /No with children <18 yearsFor peer review only 13 Primary education or less 9 years or less of education 14 Highest years of education Education level Secondary education 10 to 12 years of education 15 completed Tertiary education or more More than 12 years of education 16 http://bmjopen.bmj.com/ Employed Fully employed, part time employment, owns company, on leave from work, study 17 leave or on military service 18 Employment Employment status Retired Pensioner, prematurely retired, partly retired status 19 Retired for disability or illness Retired for injury 20 Unemployed Unemployed, housewife/man 21 Level 1 Unskilled Employees 22 Level 2 Lower skilled, non-manual workers Socioeconomic 23 Socioeconomic occupation level Level 3 Self-employed excluding independent workers 24 index Level 4 Intermediate non-manual employees on September 29, 2021 by guest. Protected copyright. 25 Level 5 Highest tier non-manual employees 26 Have you ever smoked or used Never smoked No not even tried it, yes but only tried it, smoked now and then (like at parties), 27 Tobacco Use snuff Former smoker Smoked regularly, snuffed regularly, smoke now and then (like at parties) 28 Current smoker Smoke regularly, smoke at parties, snuff now and then, snuff regularly 29 Any movement Do you have any physical Yes/no Yes/ No 30 impairment handicap 31 Do you need assistance with 32 Disability personal care/ Yes/No Yes /No 33 shopping,/cooking/mobility/ 34 Less than average Almost no exercise, light exercise, much less exercise than average, less than average 35 Exercise How much do you exercise; what Average Regular medium exercise, average amount of exercise 36 fits your annual exercise pattern More than average Hard physical exercise, more exercise than average, much more exercise than 37 normal, maximum amount of exercise 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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20 21 Supplementary Table 4. Association of dog ownership with initiation of lipid lowering medication. This compares the main analysis as shown in Table 2 22 23 with a modified analysis that censored participants at an event of angina or heart failure. Cox regression models with hazard ratios (HR) and 95% confidence

24 interval (CI) are reported. on September 29, 2021 by guest. Protected copyright. 25 26 Lipid lowering N treated Time at risk Model 1* Model 2§ 27 medication 28 Without censoring 276,691 11,508,349 1.03 (1.02-1.04) 1.02 (1.01-1.04) 29 30 With censoring 243,797 11,482,789 1.03 (1.02-1.04) 1.02 (1.01-1.04) 31 32 33 34 *Model 1. Age and sex adjusted 35 §Model 2. National cohort: Adjusted for sex, age, type of family, area of residence, population density, marital status, region of birth, income, education level, latitude of residence. 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Supplementary Table 5. Additional baseline characteristics of 10,110 Swedish adults in the Swedish Twin Register. Information is based on persons who 4 participated in the TwinGene project designed to enhance the Screening Across the Lifespan Twin (SALT) questionnaire-based sub-study in the Swedish 5 6 Twin Register with biologic specimens. Numbers and % are reported unless stated otherwise. Clinical information was taken during TwinGene study (2004- 7 2008), dog ownership status on the date of clinical examination and other non-clinical details extracted from the SALT questionnaire (1998-2002). 8 9 Non-dog Mixed pedigree dog Active dog breed 10 All Dog owners owners owners owners 11 Participant characteristics n n=10,110 n=484 n=9,626 n=141 n=143 (100%) (5.0%) 12 For peer review(95.0%) only (1.4%)* (1.4%)* 13 Employed 6,875 (68.0) 6,541 (68.0) 334 (69.0) 97 (68.8) 93 (65.0) 14 Retired 2,066 (20.4) 1,992 (20.7) 74 (15.3) 18 (12.8) 29 (20.3) Employment status 10,110 15 Sick leave or illness 875 (8.7) 818 (8.5) 57 (11.8) 18 (12.8) 16 (11.2)

16 Unemployed 294 (2.90) 275 (2.9) 19 (3.9) http://bmjopen.bmj.com/ 8 (5.7) 5 (3.5) 17 Unskilled labor 2,458 (24.3) 2,351 (24.4) 107 (22.1) 32 (22.7) 27 (18.9) Lower non-manual labor 3,373 (33.4) 3,205 (33.3) 168 (34.7) 57 (40.4) 43 (30.1) 18 Self-employed 430 (4.3) 404 (4.2) 26 (5.4) 6 (4.3) 6 (4.2) 19 Profession† 10,110 Intermediate non-manual 2,539 (25.1) 2,411 (25.0) 128 (26.4) 32 (22.7) 46 (32.2) 20 labor 21 Higher non-manual 1,310 (13.0) 1,255 (13.0) 55 (11.4) 14 (9.9) 21 (14.7) 22 employee 23 Independent 10,100 (99.9) 9,616 (99.9) 484 (100.0) 141 (100.0) 143 (100.0) Type of housing or 2

10,110 Assisted living 6 (0.1) 6 (0.1) 0 (0.0) on September 29, 2021 by guest. Protected copyright. 0 (0.0) 0 (0.0) 24 accommodation Other 4 (<0.0) 4 (<0.0) 0 (0.0) 0 (0.0) 0 (0.0) 25 Biochemical Variables 26 C-Reactive Protein 9,553 Median (IQR) 1.7 (0.8-3.4) 1.7 (0.8-3.4) 1.8 (0.8-3.2) 2.0 (0.9-3.5) 1.6 (0.7-3.1) 27 LDL-Cholesterol 9,727 Mean (SE) 3.9 (0.9) 3.9 (0.9) 3.8 (0.9) 3.8 (0.9) 3.9 (0.9) 28 HDL-Cholesterol 10,109 Mean 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 1.4 (0.4) 29 Triglyceride (Fasting) 9,261 Median 1.1 (0.8-1.6) 1.1 (0.8-1.6) 1.1 (0.9-1.6) 1.2 (0.9-1.6) 1.2 (0.9-1.5) 30 Glucose (Non-Diabetic) 9,256 Median 5.3 (5.0-5.7) 5.3 (5.0-5.7) 5.2 (5.0-5.7) 5.3 (5.0-5.8) 5.3 (5.0-5.7)

31 HbA1c 10,097 Mean 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.8 (0.6) 4.7 (0.5) 32 Body Mass Index 9,618 Mean 25.9 (4.0) 25.9 (4.0) 26.0 (4.0) 26.3 (4.4) 26.0 (3.8) 33 Waist-Hip ratio 9,937 Mean 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 34 Blood pressure measurements 35 Mean systolic BP (all participants) Mean 138.1 (19.5) 138.2 (19.5) 136.0 (19.2) 139.4 (20.3) 136.2 (18.1) Mean diastolic BP (all 36 8010 Mean 82.2 (10.5) 82.2 (10.4) 82.6 (10.9) 84.8 (11.4) 82.7 (10.4) participants) 37 Pulse pressure (all participants) Mean 55.9 (15.4) 56.0 (15.4) 53.4 (13.6) 54.6 (13.9) 53.5 (12.5) 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from

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1 2 3 Mean systolic BP (On BP Mean 144.9 (18.8) 144.9 (18.9) 144.9 (17.3) 149.4 (14.9) 142.0 (15.8) 4 treatment) Mean diastolic BP (On BP 1,970 5 Mean 83.9 (10.7) 83.8 (10.8) 85.0 (9.2) 84.5 (8.4) 85.6 (9.3) 6 treatment) Pulse pressure (On BP treatment) Mean 61.0 (16.0) 61.1 (16.1) 60.0 (13.8) 65.0 (10.1) 56.4 (12.2) 7 Excellent 3,501 (34.9) 3,330 (34.9) 171 (35.7) 33 (23.6) 58 (40.8) 8 Good 5,330 (53.2) 5,085 (53.3) 245 (51.1) 79 (56.4) 73 (51.4) Self-reported health status 10,110 9 Average 963 (9.6) 914 (9.6) 49 (10.2) 19 (13.6) 8 (5.6) 10 Not so good 227 (2.3) 213 (2.3) 14 (2.9) 7 (5.0) 3 (2.1) 11 Blood Pressure Medication 10,110 Number on treatment (%) 2,099 (20.8) 2,010 (20.9) 89 (18.4) 31 (22.0) 22 (15.4) 12 Lipid Modifying Medication 10,110 Number on treatment (%) 918 (9.1) 880 (9.1) 38 (7.9) 14 (9.5) 13 (8.3) Diabetes Medication 10,110 ForNumber on treatmentpeer (%) 305 review (3.0) 293 (3.0) only12 (2.5) 5 (3.5) 5 (3.5) 13

14 *-Proportion of this breed of total population 15 †-Defined according to Budoki et al.8 16 ‡-Assisted living which includes living in http://bmjopen.bmj.com/ 17 BP- Blood Pressure 18 19 20 21 22 23

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1 2 3 Supplementary Table 6: Association of dog ownership with initiation of medication for hypertension, dyslipidaemia and diabetes. Shown for assuming 10- 4 year life-span of dog and a sensitivity analyses at 8-year and 12-year life-span of dog. 5 6 Medication Assuming 10-year life-span of dog Assuming 8-year life-span of dog Assuming 12-year life-span of dog 7 8 Sex-age Fully-adjusted Sex-age Fully-adjusted Sex-age Fully-adjusted 9 adjusted model model adjusted model model adjusted model model 10 11 Hypertension 1.02 (1.01-1.03) 1.02 (1.01-1.03) 1.02 (1.01-1.03) 1.01 (1.00-1.02) 1.03 (1.02-1.04) 1.02 (1.01-1.03) 12 For peer review only 13 Dyslipidemia 1.03 (1.02-1.04) 1.02 (1.01-1.04) 1.02 (1.01-1.04) 1.02 (1.00-1.03) 1.03 (1.02-1.04) 1.02 (1.01-1.04) 14 15 Diabetes 0.91 (0.89-0.94) 0.98 (0.95-1.01) 0.90 (0.88-0.93) 0.97 (0.94-1.00) 0.92 (0.90-0.94) 0.99 (0.96-1.02)

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1 2 3 4 5 Supplementary Table 7. Stepwise addition of covariates into TwinGene model. Odds ratios (OR) and confidence intervals (CI) for associations of dog 6 ownership and prevalent drug prescriptions for hypertension, dyslipidemia and type 2 diabetes (n=10,110). * 7 8 9 Prescription Medication N on treatment Model 1 Model 2 Model 3 Model 4 Model 5 Model 6 Model 7 10 11 Anti-hypertensive drugs 2,223 0.96 (0.75-1.21) 0.94 (0.74-1.20) 0.95 (0.74-1.20) 0.92 (0.72-1.18) 0.90 (0.70-1.15) 0.90 (0.71-1.15) 0.90 (0.70-1.15) 12 Lipid lowering drugs 963 For0.92 (0.65 peer-1.29) 0.92 (0.65 -1.29)review 0.92 (0.66-1.29) 0.90only (0.64-1.26) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 0.87 (0.62-1.22) 13 14 Glucose lowering drugs 318 0.89 (0.49-1.61) 0.90 (0.50-1.63) 0.91 (0.50-1.65) 0.90 (0.50-1.63) 0.80 (0.44-1.46) 0.80 (0.44-1.46) 0.78 (0.43-1.43) 15

16 http://bmjopen.bmj.com/ 17 *Model 1, 2 and 7 were reported in the main manuscript Table 2 18 Model 1. Adjusted for age and sex Model 2. Adjusted for sex, age, type of family, area of residence, population density, marital status, education level and latitude of residence 19 Model 3. Model 2 plus professional level 20 Model 4. Model 3 plus employment status 21 Model 5. Model 4 plus Charlson comorbidity index 22 Model 6. Model 5 plus disability 23 Model 7. Full twin model - Model 6 plus tobacco use

6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 1.018 0.000 1.009 1.028 9 10 Sex 11 Male 12 Ref 13 Female 0.945 0.000 0.939 0.950 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer0 .90review4 0.000 only0.895 0.912 19 20 Divorced 0.993 0.091 0.986 1.001 21 Widowed 22 1.064 0.000 1.053 1.076 23 Children in home 24 25 No Ref 26 Yes 27 0.922 0.000 0.915 0.930 28 Area of Residence 29 30 Norrland Ref 31 Svealand 0.959 0.000 0.946 0.972 32 33 Götaland 0.912 0.000 0.895 0.929 34 35 Population density 1.000 0.203 0.998 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 40 0.955 0.000 0.949 0.962 41 Tertiary level 0.832 0.000 0.826 0.839 42 43 Country of birth 44 Sweden on September 29, 2021 by guest. Protected copyright. 45 Ref 46 Other Nordic countries 1.143 0.000 1.128 1.157 47 48 Non-Nordic countries 1.010 0.114 0.998 1.022 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 0.994 0.195 0.985 1.003 54 Income level 3 55 0.995 0.297 0.986 1.004 56 Income level 4 0.991 0.056 0.982 1.000 57 58 Income level 5 (highest tier) 0.986 0.004 0.977 0.995 59 Latitude of residence 60 1.000 0.000 1.000 1.000

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6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 1.024 0.000 1.011 1.036 9 10 Sex 11 Male 12 Ref 13 Female 0.773 0.000 0.767 0.779 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer0 .83review5 0.000 only0.825 0.846 19 20 Divorced 0.992 0.117 0.982 1.002 21 Widowed 22 1.022 0.004 1.007 1.038 23 Children in home 24 25 No Ref 26 Yes 27 0.891 0.000 0.881 0.901 28 Area of Residence 29 30 Norrland Ref 31 Svealand 1.005 0.597 0.987 1.024 32 33 Götaland 0.928 0.000 0.905 0.952 34 35 Population density 1.000 0.000 0.999 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 40 0.963 0.000 0.954 0.972 41 Tertiary level 0.796 0.000 0.787 0.804 42 43 Country of birth 44 Sweden on September 29, 2021 by guest. Protected copyright. 45 Ref 46 Other Nordic countries 1.169 0.000 1.150 1.189 47 48 Non-Nordic countries 1.195 0.000 1.177 1.213 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 1.000 0.962 0.988 1.012 54 Income level 3 55 1.004 0.504 0.992 1.016 56 Income level 4 1.010 0.104 0.998 1.022 57 58 Income level 5 (highest tier) 1.005 0.450 0.992 1.018 59 Latitude of residence 60 1.000 0.813 1.000 1.000

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6 Haz. Ratio P>z [95% Confidence Interval] 7 8 Dog owner 0.982 0.193 0.954 1.009 9 10 Sex 11 Male 12 Ref 13 Female 0.546 0.000 0.536 0.556 14 15 Marital status 16 Married/ cohabiting Ref 17 18 Never Married For peer1.244 review 0.000 only1.215 1.274 19 20 Divorced 1.196 0.000 1.171 1.223 21 Widowed 22 1.290 0.000 1.248 1.334 23 Children in home 24 25 No Ref 26 Yes 27 0.965 0.002 0.944 0.988 28 Area of Residence 29 30 Norrland Ref 31 Svealand 0.909 0.000 0.8741825 0.946 32 33 Götaland 0.883 0.000 0.8366307 0.932 34 35 Population density 0.999 0.000 0.998 1.001 36 Education http://bmjopen.bmj.com/ 37 38 Primary level Ref 39 Secondary level 40 0.877 0.000 0.861 0.894 41 Tertiary level 0.635 0.000 0.620 0.650 42 43 Country of birth 44 Sweden on September 29, 2021 by guest. Protected copyright. 45 Ref 46 Other Nordic countries 1.116 0.000 1.076 1.159 47 48 Non-Nordic countries 1.952 0.000 1.900 2.004 49 Income 50 51 Income level 1 (lowest tier) Ref 52 53 Income level 2 0.919 0.000 0.896 0.941 54 Income level 3 55 0.845 0.000 0.824 0.866 56 Income level 4 0.777 0.000 0.757 0.797 57 58 Income level 5 (highest tier) 0.702 0.000 0.683 0.722 59 Latitude of residence 60 1.000 0.001 1.000 1.000

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 Supplementary Figure 1: Study population 6 7 8 9

10 3,412,946 Swedish residents aged between 45 11 and 80 years on October 1st 2006 12 13 14 15 16 17 12,105 individuals from 11,298 individuals with unverified 18 the TwinGene cohort aged For peer review oronly re-used identification numbers 19 and/or incomplete education 20 47-80 years records 21

22 23 1,373 individuals had a 24 history of cardiovascular 137,306 individuals migrated to 25 disease 26 Sweden after 1991 or emigrated 27 before study start 28 29 622 with incomplete or 30 missing data 31 531,658 individuals had a history 32 of cardiovascular disease 33 34 35 36 10,110 individuals (5.0%) dog owners) with 705,819 individuals had a history http://bmjopen.bmj.com/ 37 baseline measurements of cardiovascular risk of using anti-hypertensive drugs,

38 factors lipid-modifying drugs or blood 39 glucose lowering drugs 40 41 42 43 2,026,865 eligible individuals (14.6% dog 44 owners) followed up to outcome, death, on September 29, 2021 by guest. Protected copyright. 45 emigration or study end December 31st 2012 46

47 48 49 50 51 52 53 54 55 56 57 58 59 60

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32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23

1 2 3 Supplementary Figure 4. Hazard ratios (HR) and 95% confidence intervals (CI) for the association 4 of dog ownership and time to initiation of medication for hypertension, dyslipidaemia and type 2 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 diabetes examining associations in breeds previously identified to be associated with ‘active dog 9 7 breeds’ (combining Terriers, Scent Hounds, Pointing dogs and Retrievers) and mixed pedigree dogs 8 and adjusted for age, sex, marital status, presence of children in the home, population density, area of 9 residence, education level, region of birth, income and a correction for latitude of residence. 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 References 4 BMJ Open: first published as 10.1136/bmjopen-2018-023447 on 7 March 2019. Downloaded from 5 6 7 1. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, et al. The Swedish personal identity number: 8 possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24(11):659- 9 67. doi: 10.1007/s10654-009-9350-y [published Online First: 2009/06/09] 10 11 2. Ganzeboom HB, De Graaf PM, Treiman DJ. A standard international socio-economic index of 12 occupational status. Social science research 1992;21(1):1-56. 13 3. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in 14 longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373-83. [published 15 Online First: 1987/01/01] 16 4. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson comorbidity index and score 17 for risk adjustment in hospital discharge abstracts using data from 6 countries. American 18 journal of epidemiologyFor peer 2011;173(6):676 review-82. only 19 20 5. Lichtenstein P, De Faire U, Floderus B, et al. The Swedish Twin Registry: a unique resource for 21 clinical, epidemiological and genetic studies. J Intern Med 2002;252(3):184-205. [published 22 Online First: 2002/09/25] 23 6. Magnusson PK, Almqvist C, Rahman I, et al. The Swedish Twin Registry: establishment of a biobank 24 and other recent developments. Twin Res Hum Genet 2013;16(1):317-29. doi: 25 10.1017/thg.2012.104 [published Online First: 2012/11/10] 26 7. Lakemedelsverket. Prevention of atherosclerotic cardiovascular disease - Treatment 27 recommendation. https://lakemedelsverketse/upload/halso-och- 28 29 sjukvard/behandlingsrekommendationer/080313_primarpreventionpdf 2006 30 8. Bukodi E, Erikson R, Goldthorpe JH. The effects of social origins and cognitive ability on educational 31 attainment. Acta Sociologica 2014;57(4):293-310. doi: doi:10.1177/0001699314543803 32 9. Mubanga M, Byberg L, Nowak C, et al. Dog ownership and the risk of cardiovascular disease and 33 death - a nationwide cohort study. Sci Rep 2017;7(1):15821. doi: 10.1038/s41598-017-16118- 34 6 [published Online First: 2017/11/19] 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 29, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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