This article isThis article by protected copyright. All rights reserved. 10.1002/hep.30804 differences thisbetween andVersion version the ofRecord.cite Please this asdoi: article the through copye This article acceptedhas been for publication andundergone fullpeer review buthasnotbeen Helsinki, Finland. Finland Oulu, Oulu, of University MRCOulu, and Finland. Kuopio, Finland, Eastern of University Hospital and University Kuopio Medicine, Nuclear and Clinical of Physiology Ad and Children Hospital for Cardiology, Finland. Tampere, ofTampere, University Life Sciences, and Medicine Center Research Cardiovascular andFinnish Laboratories Fimlab Clinical Chemistry, U London, London, College University Health, and Public Epidemiology of Department Finland. Tampere, Hospital, Australia. Hobart, Tasmania, Turku, Finland. Hospital, University Turku Finl Turku, Turku, of University and Health, Turku, Finland. Finland; 1 PhD MD, PhD Kivimäki, FMedSci Magnussen, PhD Tomi T.Laitinen, PhDMD, in Risk Cardiovascular inadulthood:the liver fatty and riskof disadvantage socioeconomic Childhood :Original Article type 0000 ID: (Orcid TLAITINEN DR. TOMI 1 Accepted Tur University of Medicine; Cardiovascular Preventive Appliedand of Centre Research Article 12 ; Markus Juonala, PhD MD, Centre for Population Health Research, University of Turku and Turku University Hospital, Hospital, University Turku and ofTurku University Research, Health forPopulation Centre 9 ; Päivi Tossavainen, MD, PhD

2 Paavo Nurmi Centre, Sports & Exercise Medicine Unit, Department of Physical Activity Activity Physical of Unit,Department Medicine &Exercise Sports Nurmi Centre, Paavo 12 Department of Medicine, University of Turku and Division of Medicine, Turku Turku Medicine, of Division and ofTurku University Medicine, of Department diting, typesetting, pagination and proofreading process, to whichmay lead 1,4

6 ; Joel Nuotio, MD, PhD ; Terho Lehtimäki, MD, PhD

10 Department of Pediatrics, Oulu University Hospital, PEDEGO Resear University PEDEGO Oulu Hospital, Pediatrics, of Department 6 5 Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Finland; Helsinki, Helsinki, University of Medicine, of Faculty Clinicum, Young Finns Study Young Finns Department of Pediatrics, University of Tampere and Tampere University University Tampere and ofTampere University ofPediatrics, Department 1, 2 ; Jussi Vahtera, MD,PhD - 0003 1, 12 olescents, University of Helsinki, Helsinki, Finland. Helsinki, ofHelsinki, University olescents, 4 Menzies Institute for Medical Research, University University of Research, Medical Institute for Menzies and. ;Olli T.Raitakari, MD, PhD - 2771 10 3 ; Jaana Pentti, BSc Department of Public Health, University of Turku and and Turku of University Health, Public of Department 11 - 1 8955) ; Nina Hutri Clinicum, Faculty of Medicine, University of Helsinki, ofHelsinki, University ofMedicine, Faculty Clinicum,

7

; Eero Jokinen, MD, PhD

3 ; Katja Pahkala, PhD - Kähönen, MD, PhD 3,11 8 Department of Pediatric Pediatric of Department

Jorma S.A.Viikari, MD, 1,13

-

8 Tampere, Faculty Faculty of Tampere, ; K.

5 1, 2 Tomi Laitinen, ku, Turku, Turku, ku, ; Mika

7 Department of of Department ; Costan G. 9 Department Department ch Unit This article isThis article by protected copyright. All rights reserved. Accepted andJarno VilleAalto, Ikonen, Johanna Lisinen, Irina Kartiosuo, Noora biostatisticians and study; longitudinal this in adults and children both as participated who persons the points; time measurement all at data collected that teams the thank We Acknowledgement (R01AG056477). onAging Institute National US the and NordForsk, (311492), Finland of Academy the Sciences, Life of Institute Helsinki by supported sup Foundation. Supporting Hospital University Tampere project); MULTIEPIGEN for 742927 (grant Council Research European and TAXINOMISIS); for 755320 (grant 2020 Horizon EU and Association; F Gyllenberg Ane and Signe Foundation; Jahnsson Yrjö Foundation; Aaltonen Emil Foundation; Tuberculosis Tampere Foundation; Juselius Sigrid The Foundation; Cultural Finnish Research; Cardiovascular for Foundation Finnish Foundation; Nurmi Vainio Juho X51001); (grant Hospitals University Turku and Tampere Kuopio, of Article area Responsibility Expert the of Financing Research State Competitive Finland; of Institution Insurance 286284, grants 12158 Finland: 126925, (Eye), of 134309 Academy the by supported financially been has Study Finns Young The of Funding Sources Turku, Kiinam of University Medicine, Cardiovascular Preventive and Centre Applied of Research Laitinen, Tomi T. correspondence Address for Turku, Finland. Hospital, University Turku Turkuand of Finland. Turku, Hospital, University ported by a National Heart Foundation of Australia Future Leader Fellowship (100849). MK is is MK (100849). Fellowship Leader Future Australia of Foundation Heart National a by ported yllynkatu 10, FIN 10, yllynkatu s

4, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Social the (Skidi); 41071 and (Gendi), 117787 (Salve), 129378 124282, 4, - 20520 Turku, Finland. E Turku, Finland. 20520

13 Departm Kankaanranta for data management and statistical advice. statistical and datamanagement for Kankaanranta oundation; Diabetes Research Foundation of Finnish Diabetes Finnish of Foundation Research Diabetes oundation;

ent of Clinical Physiology and Nuclear Medicine, University University Medicine, andNuclear Clinical Physiology ent of

- mail mail [email protected]

Foundation; Paavo Paavo Foundation;

CGM is is CGM This article isThis article by protected copyright. All rights reserved. study Population Risk factors; status; Socioeconomic steatosis; Hepatic study; Key Longitudinal Words: risk multiple with associated (7%). consumption meat red (14%), and (15%), triglycerides activity physical (20%), (29%), insulin pressure systolic blood (40%), index body mass ( circumference waist liverincluded fatty with disadvantage socioeconomic childhood linking risk factors Adulthood was disadvantage (1.33[1.09 lowbirth weight and insulin, elevated index, body mass high including fattyliver, of risk factors childhood age,sex,and adjustment for 1.42[1.18 interval] confidence ratio[95% liver (risk fatty of increased risk with an associated was disadvantage socioeconomic childhood High adulthood. life 34 (2011) at ages up lastfollow the during ultrasound determinedby liver was Fatty disadvantage. socioeconomic low residen participants’ in circumstances and socioeconomic position socioeconomic parents’ from data using assessed was disadvantage socioeconomic Childhood Follow Study. Finns RiskinYoung Cardiovascular 3 aged participants 2,042 comprised population thisof link. mediators possible as offatty liver risk factors tested adulthood and fatty liver of association the We examined understood. fattyliverarepoorly foradulthood earlyriskfactors failure,but ofliver cause a preventable is Fatty liver ABSTRACT None Interest of Conflicts

Accepted- Article styl

e variables, were assessed in clinical examinations. were assessed e variables,

proportion mediated of the total effect of childhood socioe childhood of the totaleffect of mediated proportion - 49 years. Childhood and adulthood risk factors, including metabolic biomarkers and and biomarkers metabolic including riskfactors, adulthood and Childhood 49 years. also associated with the development of risk factors of fatty liver in adulthood. adulthood. liverin offatty riskfactors of the development associatedwith also

factors of fatty liver and increased likelihood of fatty liver in adulthood. adulthood. liverin of fatty likelihood andincreased liver offatty factors

Conclusion: childhood socioeconomic disadvantage with adulthood adulthood with disadvantage socioeconomic childhood - - - 18 years at baseline (1980) from the longitudinal the longitudinal (1980) from at years baseline 18 up with repeated clinical examinations was 31 years. 31 years. was examinations clinical with repeated up 1.62],P=0.005). High childhood socioeconomic socioeconomic childhood High 1.62],P=0.005). - 1.70

Childhood socioeconomic disadvantage was was disadvantage socioeconomic Childhood ],P=0.0002). This association was robust to wasrobust This association ],P=0.0002). tial neighborhoods, categorized as high versus high categorized asversus neighborhoods, tial

18.9 % of the participants had fatty liver in fatty had theof participants 18.9 %

conomic disadvantage 45% disadvantage conomic

The study study The

),

This article isThis article by protected copyright. All rights reserved. Accepted fattyliver.of risk factors adulthood byknown mediated liver was analysis used mediation addition, we inmid later decades three measured liver withfatty isassociated SED, neighborhood (SED to aimed specifically adulthood. liverin with fatty associated was disadvantage neighborhood Risk Cardiovascular the longitudinal from status. personalsocioeconomic oftheir independent areas, more in affluent living those countries forind problems health public major are mortality and inmorbidity disparities Socioeconomic Article fatty liver. riskfactorsforadult as inchildhood and high BMI high insulin, birth weight, low identified previously riskfa behavioral as beenconsidered have habits dietary unhealthy liver. riskoffatty increased with areassociated dyslipidemia, by transplantation forliver indication common themost become to predicted isalso and countries industrialized worldwide. people 20%of approximately Non INTRODUCTION - ) on adult fatty liver. We tested whether childhood SED, characterized by parental and childhood childhood parental and by SED, characterized childhood whether We tested liver. adult fatty ) on alcoholic fatty liver disease (also known as ‘fatty live as‘fatty known (also disease liver fatty alcoholic . 6,7 5

People living in disadvantaged areas generally experience worse health outcomes than than health outcomes worse experience generally areas disadvantaged living in People 2030.

examine the prospective association of childhood socioeconomic disadvantage disadvantage socioeconomic childhood of association prospective the examine 2 2 In adults, obesity and metabolic disturbances, such as insulin resistance and and insulin resistance as such disturbances, metabolic and obesity In adults, 11 to determine if the as the determineif to 1 in Young Finns study, we r we study, Finns Young in

It is the most common cause of chronic liver disease in disease liver chronic cause of common themost It is r’) is a major public health concern affecting affecting concern public health major r’) isa sociation between childhood SED and fatty andfatty SED childhood between sociation 2

In addition, physical inactivity and inactivity and physical addition, In

ctors of fatty liver. ctors offatty ecently showed that that lifetime showed ecently 10

In the present study, we present study, In the - adulthood. In adulthood. 3 - 4

8,9 In addition, we we addition, In

Using data Using data ustrialized ustrialized This article isThis article by protected copyright. All rights reserved. liver. ho registries, discharge hospital national liver18.9%). fatty of (prevalence fatty (N =1,657) liver without and (N=385) with those groups; characte participant’s to blinded ultrasonographer trained walls. accordi transducers. abdominal MHz 4.0 adult USA) with View, CA, Mountain (Acuson, mainframes ultrasound 512 Sequoia and protocol validated usinga 2011 imaging ultrasound by measured was Fatty liver Fattyliver Outcome: committees. years. inch onSED data provided attended. conducted. follo several 1980, Finland. Since inpartsof areas different the study of register the national from chosen randomly were participants These participated. years 18 aged 3to CVD. underlying factors multicenter follow onongoing is Study Finns Young in Risk The Cardiovascular Participants METHODS

Acceptedspitals, Article

13

All participants provided written informed consent, and the study was approved by local ethics ethics bylocal approved thestudy was and consent, informed written provided All participants

ng to liver ng According to these criteria the presence of hepatic steatosis was assessed visually by a one visuallyby assessed was steatosis ofhepatic the presence criteria these to According

we were able to verify that none of the participants had viral or autoimmune causes of fatty of causes autoimmune viralor had participants the of none verify that to were able we In this study, t study, this In 12

The latest The follow latest

- to - kidney contrast, parenchymal brightness, deep beam attenuation and bright vessel vessel bright and beam attenuation deep brightness, parenchymal contrast, kidney

12 he sample comprised sample he The cross first The ildhood and liver ultrasound data at the2011follow at data liver ultrasound and ildhood - up survey was performed in 2011, when 2,063 of the original participants the participants original of when 2,063 2011, in performed was up survey containing data on those onthose containing data - sectional survey was conducted in 1980, when 3,596 individuals individuals when 3,596 in1980, conducted was sectional survey

2,042 participants 2,042

of the liver performed for 2,042 study participants in in participants study 2,042 for theliverperformed of 13

Evaluation of hepatic steatosis was performed performed was hepatic steatosis of Evaluation ristics. Participants were categorized into two into categorized were Participants ristics.

discharged from inpatient care in care inpatient from discharged

aged 3 aged w - up studies have been havebeen up studies - 18 years at baseline (1980) atbaseline years 18 - up study to assess risk to assess study up - up, when aged 34 up, when aged By using By using - 49

who who This article isThis article by protected copyright. All rights reserved. of the development SED on neighborhood childhood and SED parental of contribution high( to categorized SED Childhood also assessed was SED neighborhood analyses, cumulative time theresidential up bysumming computed (N=1733) was childhood in SED Neighborhood coordinates. longitude and using latitude 2013 between 1980and moves of withdates addresses onthereside the linked was data The Centre. Register Population the Finnish from were obtained ofmoves withdates history residential participants’ the study, this SED in the neighborhood SED.Todetermine neighborhood ahigher indicating all 3 z value across z as standardized (an indicato ownership ofhome level,theproportion ofeducational a low with adults of the proportion from isderived Finland grid in meter 250×250 foreach score The residents. 10 adult with least at ingrids Finnish residents provideaneig can database national metergrid 250×250 This grid database. Finland’s the Statistics from obtained were SED neighborhood Dataon same 3 indicators. the based on wi indicators, the 3 - as coded was unemployment which was exception theonly SD=1), (mean=0, standardized was indicator the of unemployment variable) and (continuous income household mean education), thehighest with the parent (in yearsfor education the parent's of based the length population the i.e.SEDofadult SED, neighborhood SED and onparental based was SED childhood of Assessment disadvantage Childhood socioeconomic Accepted Articlemean of the SED was parental scorefor overall The 0otherwise. and ofunemployment ahistory 1 for in the childhood residential neighborhoods. neighborhoods. residential the childhood in neighborhood SED score in each address in each address SED score neighborhood

was calculated as the mean of parental SED and childhood neighborhood SED and SED neighborhood childhood SED parental and of the mean calculated was as - score, as previously described. previously as score, - th a higher score indicating higher parental SED (N=2041). (N=2041). SED parental higher indicating th a higher score scores, the national mean being 0 and standard deviation 1, with with 1, deviation andstandard being 0 mean thenational scores, > 0; N=995) and low (<0; N=1047) for the analyses. To examine the relative relative the To examine theanalyses. for N=1047) (<0; low N=995) and 0; r of wealth), and the unemployment rate, with each of the 3 variables ofthe 3variables with each rate, the unemployment wealth),and r of

ntial neighborhoods to the cohort participants’ home the cohortparticipants’ to neighborhoods ntial from the age of the age from 10

The SED score for each neighborhood is the mean isthe mean each neighborhood for SED score The from the age of the age from Parental SED Parental

3 to 18 years (N=1533) to 18years 3

parent or parents (yes vs no). Each Each no). vs (yes parents or parent

6 to 21 years. 6 to21years. was constructed using 3 indicators indicators 3 using constructed was hborhood SED score for all for SED score hborhood Neighborhood SED Neighborhood In sensitivity In sensitivity a higher score a higher

fatty liver, we fatty - weighted weighted

was was 10

This article isThis article by protected copyright. All rights reserved. Acceptedtape t non a using line midaxillary atthe the lowest rib iliac crestand between midway wasmeasured circumference Waist squared. meters in byheight divided kilograms follow theof adulthood from variable the of mean value the indicates follow theadulthood in were measured liver. fatty adulthood SED and childhood of cohorts andother inthis fatty liver all meat, ofred consumption and alcohol, of consumption activity, smoking, physical triglycerides, pressure, blood systolic insulin, circumference, BMI, waist mediators) (Possible fatty liver of factors risk Adulthood was Finland) Western or (Eastern placeofbirth on Information boys. g for and<2,900 g girls for were<2,850 theanalyses in weight used lowbirth for points cut of Article( clinic records by well verified was birth weight on Data methods. enzymatic standard with measured insulin was Serum squared. inmeters height by divided kilograms weight in as calculated BMI and were measured study, cohort liver inthis bir and BMI, insulin liver fatty of factors Childhood risk asacut using [N=613]) 0 low 4 constructed a also o the nearest 0.1 cm. Blood pressure was measured using a random zero sphygmomanometer in in sphygmomanometer zero random using a measured pressurewas cm. Blood 0.1 thenearest o

childhood BMI and insulin indicates the baseline level of thebaseline level insulin indicates BMI and childhood N=1,752). Low birth weight was defined as birth weight <10th percentile. <10th weight asbirth defined was birthweight Low N=1,752). 5 and were considered as childhood risk factors in the present study. study. in present the riskfactors aschildhood considered and were th weight have previously been identified as childhood risk factors of adulthood fatty fatty ofadulthood risk factors aschildhood identified been previously weighthave th - category variable (high variable category - ups. Height and weight wer weight and ups. Height - off point for both components of childhood SED. childhood of bothcomponents for point off 3

- 4,13 , were considered as possible mediators between the association association the between mediators aspossible were considered , - ups in 2001, 2007, and 2011. In the present study the present In and2011. 2007, 2001, ups in

Adulthood risk factors of fatty liver (possible mediators) (possible fattyliver of risk factors Adulthood - high [N=482], high [N=482], high these

e measured, and BMI was calculated as weight in as calculated was and BMI e measured, three adulthood follow adulthood three

previously shown as adulthood risk factors of factors risk asadulthood shown previously

- - stretch plastic covered cloth measuring measuring covered cloth plastic stretch obtained with a questionnaire. with a obtained the variable in 1980. variablein the low [N=379], low [N=379], low - ups, or daily smoking in any any in dailysmoking or ups,

- high [N=258], andlow [N=258], high

Height and weight weight and Height In the present present the In 5 The sex The , the

mediator mediator - specific specific - baby - This article isThis article by protected copyright. All rights reserved. The liver. and fatty SED childhood association between for risk ratio the to estimate into account Acceptedbo total effect, For adulthood. statusin theirrisk due to SED that is childhood to high exposed among those fattyliver of risk to theexcess refers indirect effect mediato the to exposure of the level where ascenario liver fatty in SED and childhood between association effects. total and effects, indirect effects, natural ratioscale. the risk on wereestimated effects causal analysis mediation traditional by macro presented SAS using a (mediators). liver offatty factors risk adulthood liver through fatty on (exposure) SED childhood of to effects examine the analysis mediation counterfactual We used confidence their95% (RR) and relative as risks reported were The results childhood. SED in neighborhood high/low with SED parental high/low of thecombinations for variable dis askewed due to (BMI, fatty liver Article for risk factors childhood and Finland), Western or (Eastern ofbirth place sex, with age, and adjusted liver fatty adulthood SED and childhood of theassociation concerning w adulthood of Association analyses Statistical questionnaires. with obtained was consumption alcohol and consumption), (red meat habits dietary smoking, activity, physical on Information methods. enzymatic standard performed with an after drawn were samples blood venous and insulin, triglycerides serum of Forthedetermination analyses. inthe wasused 3measurements of Theaverage adulthood. r is similar among individuals exposed and non and exposed individuals similaramong r is ere

childhood and adulthood risk factors offatty liver riskfactors adulthood and childhood

insulin, examined using Poisson Poisson using examined

tribution. Similar analyses were used to examine the association of the ofthe 4 examine the association used to were analyses Similar tribution.

and low birth weight birth low and by allowing for interaction between the exposure andmediator. the exposure between interaction by allowingfor VanderWeele. regression with robust standard errors. errors. standard with robust regression ).

Insulin values were log valueswere Insulin 11

Counterfactual mediation analysis extends from the from extends analysis mediation Counterfactual The natural direct effect provides risk ratio for the riskratiofor effect provides natural direct The

The e The - th natural direct and indirect effects are taken effects indirect direct and th natural natural The SED. high childhood to exposed ffects were separated into natural direct direct into natural separated were ffects The mediation analysis was performed performed was analysis mediation The

, and overnight fast. These analyses were analyses fast. These overnight - childhood SED with fatty liver in liverin SED with fatty childhood

transformed for these analyses analyses these for transformed wer

intervals (CI). intervals e performed both unadjusted unadjusted both e performed The analyses analyses The

- category

The The This article isThis article by protected copyright. All rights reserved. p=0.01). 1.54, age,sex, adjustment for CI1.19 (95% inadulthood liver risk fatty fold of A 1 findings. these replicated measure continuous birth (Table later inadulthood combined. were analyzed the genders Thus, females. males and between similar liver was fatty SED on of that the effect indicating (P>0.05) detected was interaction significant SED*gender used. No was ofSED*gender term interaction fatty adulthood with SED ofchildhood theassociation in differences gender To examine live fatty of and risk childhood SED Association between up was31years. 3 were at participants in shown 2,042) are (n= participants ofthestudy Characteristics RESULTS at a2 were available. were not childhood from measurements whichrepeated for consumption, alcohol and werewaist onlyexceptions used.The was of18years the age before measurement available of18 the age mediator at ofthe measure childhood Table the Supplementary reported in analyses the wefurtheradjusted SED, to childhood exposure t each mediator. for percentages given is as totaleffect the of mediated proportion Accepted Article of period during the effect totheir exert began mediators adulthood potential the that he possibility

and childhood risk factors of fatty liver (BMI, insulin, low birth weight). birth low liver (BMI,insulin, offatty risk factors childhood and - performed using SAS version 9.4 (SAS institute, Inc, Cary, NC) with statistical significance inferred inferred significance withstatistical Inc, NC) institute, Cary, 9.4(SAS version SAS using performed tailed P tailed

-

value value <0.05.

- 18 years of age at baseli ofage years 18 place of birth, and childhood risk factors of fatty liver (RR 1.28, 95% CI 1.06 95% (RR1.28, fatty liver of risk factors childhood and birth, of place

1

High childhood ). This relationship remained significant after adjustment for age, sex, age, for adjustment after remained significant ).This relationship

SED was associated with increased risk of fatty liver 31 years liver fatty 31years of risk withincreased associated SED was ne ne - 1.65; p<0.0001), and the result remained similar after similar remained theresult and p<0.0001), 1.65; [mean (SD) 10.8 (SD) [mean - SD increase in childhood SED associated with 1.40 associated SED in childhood increase SD years. In case the value was missing, the last missing,the was the value Incase years. r

in adulthood in

Supplementary Supplementary

(5.0) (5.0) years]

U

se of childhood SED as a as SED ofchildhood se and t and Table 1. Table

In order to control for to In order he le he

All statistical tests tests statistical All

ngth follow of ngth liver, an

The The place place of 3 -

- for for - This article isThis article by protected copyright. All rights reserved. of study. this sensitivitythese an shown inSupplementaryadjusted Table2werefurther forchildhood level In ofthemediator. all participants with neighborhood SEDavailable the repeated analyses shown inTable In Supplementary Table Sensitivity analyses insulin, (Figure(BMI, lowbirth weight) 1b). were similar after adjustment sex,place forofand age, birth, childhood risk factors neighborhood offattychildhood SEDwiththerisk wasnotassociated liver.The alone results fattyadulthood parental SEDboth high andhighchildhood neighborhoodSED for hadanincreased risk forvariable combinationsthe oflow/high parental SED childhood. Those withlow/highin with The separate effects ofpar theassociation not mediate consumption. redmeat and7%for triglycerides, for activity, 14% waist circumference The in 1.18]), 1.12[1.06 effect indirect fornatural interval] [95%confidence ratio (risk circumference waist adulthood (Table analyses mediation performed To examine To examine Accepted Article(1.02[1.00 sulin proportions mediated of the total effect of childhood socioeconomic disadvantage were 45% for 45%for were disadvantage socioeconomic childhood effect of ofthetotal mediated proportions BMI

(1.10[1.05 possible mediators of the association between childhood SED and adulthood fatty liver fatty adulthood SED and childhood between the of association mediators possible

liver (Figure 1a). - 1.04]), physical activity (1.04[1.01 activity 1.04]), physical , 40% for BMI, 29% for systolic systolic b BMI,29%for 40%for , alyses, results the were essentially similar shown main analyses to those inthe -

1.16]), systolic blood pressure (1.08[1.04 pressure blood systolic 1.16]), 2

, Supplementary Table , Supplementary between childhood SED and adulthood fatty liver fatty and adulthood SED childhood between ental andneighborhoodSED were examined4 the using In contrast 2 ). In these analyses, theseanalyses, In ). 1 , Table , the , the to exposure high parental SED orhigh

2 from age the of , and 1, Figure respectively, dataon using - lood pressure, 20% for insulin, 15% for physical physical 15%for insulin, 20%for pressure, lood 1.08]), and red meat consumption (1.02[1.00 consumption meat red 1.08]), and 3 , andSupplementary1,wehave Figure t he following mediators were identified: mediators he following

- 1.13]), triglycerides (1.04[1.01 triglycerides 1.13]),

Alcohol consumption and smoking did smoking and consumption Alcohol

3 to18years .

. M ediation analyses - category of fatty liver - 1.06]), - 1.04]). 1.04]). , we , we - This article isThis article by protected copyright. All rights reserved. effect o detrimental the mitigate to fatty liver consumption red meat tho were riskfactors lower behavioral these for effect the total of mediated proportions the Although association. the mediate to wereobserved riskfactors, behavioral aremodifiable that consumption, (45 of measures adulthood for observed were SED childhood of the totaleffect fatty liver of factors risk behavioral as considered been have redmeat, of consumption high habits,especially dietary unhealthy and physical inactivity unknown. remain resistance insulin or adiposity of thatareindependent association the that explain mechanisms butthe liver, associated fatty also with is pressure Systolic blood 16 hav mediators observed Allthese with liver. fatty consumption redmeat activity, and physical pressure, blood risk f we In thisstudy, liver. fatty subsequent of in adulthood. riskprofile poorer liver, SED onfatty childhood of ofthe effect proportion significant mediated a risk factors Although adulthood fatty liver. robu was finding This in later adulthood. decades W DISCUSSION Adiposity and insulin resistance are considered as key factors in the pathophysiology of fattyliver. of pathophysiology inthe key factors as considered are insulin resistance Adiposity and e found that childhood SED was associated with an increased risk of developing fatty liver three liver developing fatty of increased risk withan associated SED was childhood that e found %), BMI (40%), and systolic blood pressure (29%). pressure systolic blood and (40%), %), BMI

Accepted pressure blood systolic BMI,and waist circumference, e.g. se of Article actor profile inprofile adulthood. actor

showed showed the effect of childhood SED was not entirely explained by the excess risk to to excessrisk bythe explained entirely not was SED childhood of the effect ), these data give support to interventions targeting the behavioral risk factors of riskfactors behavioral the targeting to interventions give support data ), these that low childhood SED sets an individual on a risk pathway leading to adverse adverse to leading pathway onarisk anindividual SED sets childhood low that

We found that adult measures of measures thatadult We found These results suggest that SED in early life is an important determinant determinant important early lifeis an in that SED suggest results These f a f socioeconomically socioeconomically e been previously associated with fatty liver. with fatty associated e been previously . st to adjustment for other childhood risk factors of risk factors childhood other for adjustment st to 3,4 In this study, thisstudy, In

Importantly, also physical activity and red meat meat red and physical activity also Importantly, were on the pathway linking childhood SED SED childhood linking the pathway on were

adiposity, triglycerides, insulin, systolic systolic insulin, triglycerides, adiposity, the highest proportions mediated of mediated proportions the highest (15% disadvantaged early life. disadvantaged for physical activity activity physical for high waist circumference circumference waist high 13 - 16 In addition, addition, In

and 7% 3 develop a develop

- 4,6,13 than than - 6

for for This article isThis article by protected copyright. All rights reserved. Accepted confoundi nounmeasured of assumption the addition, In outcome. the exposure of confounding correla are fattyliver) of factors (risk mediator and SED) (childhood isthatexposure analysis mediation causal inference. andsupport analyses mediation incounterfactual the assumptions disa socioeconomic neighborhood of density measurement high theobjective and adulthood, and inchildhood both characterized were who well participants the long and design, study prospective the include this of study strengths Major in childhood. cortisol, such as markers, and cellularstress physiological of levels with increased associated is violence neighborhood that reported recent study and residential diseases. chronic many with associated are andairpollution, roads contacts. quality ofsocial Article depression of pathways through functioning metabolic to contribute environment family early and SED that parental beensuggested ithas Previously, exposures. neighborhood childho SED parental low fattyliver. to adulthood SED childhood low linking pathway principal significant. remained liver fatty adulthood fatt of factors risk by adulthood entirely explained not liver was fatty adulthood SED on childhood effect of mechanisms Several potential y liver. ted, and both are also related to the outcome (fatty liver). The assumption of no unmeasured ofnounmeasured The (fatty assumption liver). relatedtotheoutcome also are both ted, and od SED should be considered as a broad concept taking into account both parental and and account parental both taking into concept a broad as considered should be SED od

In addition, In walkability have been associated with glycemic control andoverweight. control glycemic with beenassociated have walkability n or low neighborhood SED alone was associated with fatty liver suggesting that that suggesting liver withfatty associated was alone SED neighborhood low or

and after adjustments for these factors the association between SED and fatty liver fatty and SED between the association factors these for adjustments after and These findings suggest that findingssuggest These

w e were able to take into account the role of known childhood risk factors for risk factors childhood known of role the take account to were able into e 17

C haracteristics of disadvantaged neighborhoods, such as living near major major near such living as neighborhoods, ofdisadvantaged haracteristics –

outcome relationship requires that the exposure temporally precedes the precedes temporally exposure the that requires relationship outcome may underlie the findings observed in this study. inthisstudy. observed the findings may underlie

differences in childhood risk factors are not the arenot risk factors inchildhood differences 22

dvantage in childhood. Our analysis fulfilled analysis Our childhood. in dvantage

18,19 ng of the mediator ng of Further Availability of healthy food outlets food healthy of Availability , we showed that showed , we We showed that that the We showed - term follow , hostility, and poor and poor , hostility, 23

– A prerequisite for for prerequisite A 20,21 outcome outcome

In additionIn - up of the up of

neither neither - , a This article isThis article by protected copyright. All rights reserved. the esti correlated, are mediators case the in Therefore, separately. examined only this study. are population study among this chronic hepatitis of causes autoimmune or viral undiagnosed the inFinland, hepatitis autoimmune or ofviral prevalence low duetothe Thus, Finland. in ofthe disease the prevalence well to corresponds has hepatitis autoimmune of the prevalence Finland, F this limitationin potential area hepatitis chronic of causes autoimmune or viral undiagnosed hepatitis, orautoimmune viral of diagnosis hada ofthe participants that none registries discharge hospital national the verify from population for isnon imaging ultrasound ultr gradedall characteristics clinical participant’s masked for whowas trained operator study,one our In modality. dependent worldwide. and Finland from findings with prior comparable histology. to compared liver, fatty severe meta and sensitivity, haslow method general population. the of studies epidemiological use in inhibiting its complications, severe in result and may it is invasive liver fatty indetecting standard the exposure. from independent fulfilled was confounding mediator mediator, ofthe measure childhood In thisstudy, exposure no unmeasured of theassumption Further, theoutcome. precedes temporally themediator that relationship requires Accepted 0.00%, and 0.03% arelow, inland Article - analysis concluded that ultrasonography allows for reliable and accurate detection of moderate of detection accurate reliableand for allows that ultrasonography concluded analysis Third the from results - based studies into the etiogenesis of fatty liver. offatty the etiogenesis into based studies , in the counterfactual mediation analysis used by us used by analysis mediation counterfactual , inthe 24

Ultrasound imaging has also its limitations: while it provides high specificity, the highspecificity, it provides while its also limitations: has imaging Ultrasound - - mediator confounding requires that the exposure must precede the mediator. themediator. precede must exposure that the requires confounding mediator study. However, prevalence However, study. invasive, widely accessible, and cost and accessible, widely invasive, asound images, thus eliminating this potential cause of bias. Because bias.Because of cause potential this thuseliminating images, asound

the mediation analyses remained similar after additional adjustment for adjustment additional after similar remained analyses mediation the ,

thus possibly leads to underestimation of fatty liver. offatty underestimation leadsto possibly thus because it is the only way to detect inflammation orfibrosis. detect waytoinflammation itistheonly because most likely very rare and should not significantly affect the results o results affectthe significantly not andshould likelyveryrare most This study has also limitations. limitations. hasalso This study respectively .

Finally, the covariates of mediator covariatesof the Finally, supporting 26 In our study, the prevalence of fatt of theprevalence ourstudy, In . 28

that the that

In In Sweden

be

estimates for hepatitis C andh hepatitisC for estimates en reported to be to 0.01 reported en assumption of no unmeasured exposure ofnounmeasured assumption

1,27 and

26 -

effective, it is likely a reasonable choice choice likelyareasonable it is effective, Liver ultrasound is also anoperator isalso ultrasound Liver

First, liver biopsy is the criterion criterion isthe liver biopsy First, Second, ev Second, Norway 11 , multiple mediators can be be can mediators , multiple - outcome association outcome , the neighboring countries of countries , the neighboring en though we were ableto were we though en y liver was 18.9%, whichis 18.9%, was liver y - 0.02% mated pathways pathways mated 25 2 epatitis Bin epatitis

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However, However, - - f - This article isThis article by protected copyright. All rights reserved. with in individuals thesefactors risk to paid be should attention liver, special offatty riskfactors behavioral and clinical adulthood by partiallymediated liver fatty was and adulthood ofthedev environment and theliving environment at the family both directed be should liver offatty the prevention at aimed that approaches suggesting high, were inchildhood SED neighborhood SED and parental both onlywhen observed was wasindependent this later; association decades three in liver adulthood fatty of risk increased with associated was SED high childhood In summary, population. follow subsequent non and participants similar among essentially levelsto be factor baseline risk reported a to follow differential loss that it ispossible Study, Young Finns Risk in inthe Cardiovascular period study extensive resultsislimited ofour the generalizability homogeneous, socioeconomic childhood of effect total ofthe mediated the proportions theof sum and partially overlap Accepted Articlet one follow - up has occurred. However, the study group has been largely dynamic, with non with largely dynamic, hasbeen group thestudy However, occurred. up has

- up not precluding participation at a subsequent follow asubsequent at participation up not precluding disadvantage can disadvantage - ups. 31

Thus, the present study p present study the Thus,

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Fourth of of opulation is largely representative of the original original the of is largelyrepresentative opulation childhood risk factors of fatty liver offatty factors risk childhood eloping child. eloping , because our study cohort was racially wasracially cohort study our , because to European populations. populations. European to

Because Because - up. In line, we have previously previously wehave line, up. In association of childhood SED ofchildhood association disadvantaged disadvantaged F . inally

The excess risk excess The - participants at participants - participation participation , duringan early life.

This article isThis article by protected copyright. All rights reserved. Accepted Article (n/N=95/ SED and lowneighborhood SED parental sex as defined was insu index, mass (body liver fatty for factors analyses. risk childhood and the birth, of place sex, for age, for adjusted (<0) and A) (Panel unadjusted SED were Analyses low and (>0) SED high to categorized and sex, socioeconomic and neighborhood age for and neighborhood standardized SED Parental and SED). (neighborhood SED) childhood (parental in disadvantage childhood in disadvantage socioeconomic 1. Figure Figure legends

Relative risks and 95% confidence intervals of fatty liver in adulthood according to parental parental to according adulthood in liver fatty of intervals confidence 95% and risks Relative

- specific <10th percentile (<2850g for girls and <2900g for boys). Dotted line line Dotted boys). for <2900g and girls for (<2850g percentile <10th specific lin [log lin - transformed], low birth weight) (Panel B). Low birth weight weight birth Low B). (Panel weight) birth low transformed], 613

in Panel A, andn/N=80/ A, in Panel

539

in Pane

SED were both both were SED l B). l

—

low low This article isThis article by protected copyright. All rights reserved. Accepted ArticleFigure 1.

This article isThis article by protected copyright. All rights reserved. AcceptedSED mean isthe SED Childhood forboys). and<2900g girls (<2850g for [log birth, of age,sex,place for *Adjusted Article SED Childhood (SED) disadvantage socioeconomic childhood Table High Low - from from transformed], low birth weight). birth weight). low transformed], 1 .

Relative risk (RR) and 95 % confidence intervals (CI) of fatty liver (CI) offatty intervals confidence 95% and (RR) Relative risk the age

of of 6 to 21 6

of standardized standardized of

years .

Low childhood childhood Low Low birth weight was defined assex defined birthweight was Low and childhood risk factors for fatty liver (body mass index, insulin index,insulin mass (body fatty liver for risk factors childhood and

fatty liver n/N (%) n/N fatty liver 164/1047 (15.7) 221/995 (22.2) parental SED and and SED parental Cases of Cases

SED

was defined as as defined was

standardized standardized

Unadjusted model Unadjusted 1.00 (reference) 1.42 (1.18 P=0.0002 < 0 and high childhood highchildhood 0 and

- in adulthood according to to according adulthood in - 1.70) specific <10 percentile percentile <10 specific cumulative neighborhood neighborhood cumulative

RR (95%CI)

Adjusted model Adjusted 1.00 (reference) 1.33 (1.09

P=0.005 SED

-

1.62) as

>0 *

.

This article isThis article by protected copyright. All rights reserved. sex SED neighborhood cumulative themean SED is Childhood eachmediator. for percentages given is as totaleffect the of mediated proportion indirect direct and natural both effect, In total d that is SED highchildhood to exposed those among liver offatty risk the excess to effect refers indirect natural The SED. among individuals issimilar the mediator to ofexposure level where the in liver a scenario and fatty (high vslow) eff direct The natural follow the adulthood variablefrom the valueof the mean indicates Mediator Table Daily smoking Daily consumption Alcohol consumption Red meat activity Physical Triglycerides Insulin pressure Systolic blood mas Body Waist circumference mediator Adulthood Accepted. Article *p<0.05 2 . Adulthood pathways (mediators) linking childhood socioeconomic disadvantage with adulthood fatty liver. liver. fatty adulthood with disadvantage socioeconomic childhood linking (mediators) pathways Adulthood

s index s index

ect provides risk ratio (RR) and 95% Confidence interval (CI) for the association between childhood childhood between association forthe (CI) interval Confidence 95% (RR)and risk ratio provides ect

1.35 1.39 1.30 1.31 1.29 1.32 1.25 1.19 1.18 RR

from from Natural direct Natural direct

effect the 1.10 1.11 1.04 1.06 1.04 1.07 1.01 0.96 0.95 95%CI age

------1.66 1.74 1.62 1.63 1.59 1.62 1.55 1.47 1.46 of of

effects are taken into account to estimate the RR for association between childhood SED and fatty liver. The liver. fatty and SED childhood between forassociation theRR estimate to account are takeninto effects 6 to 21 years to 21 6

0.99 1.00 1.02 1.04 1.04 1.02 1.08 1.10 1.12 Natural indirect effect through through effect Natural indirect RR . Low

SED mediator

was defined as defined was 1.00 1.01 1.01 1.00 1.04 1.05 1.06 0.98 0.99 - 95%CI

ups (2001, 2007 and 2011), or daily smoking in any of the adulthood follow ofthe adulthood any in dailysmoking or and2011), 2007 ups (2001, ------1.04 1.08 1.06 1.04 1.13 1.16 1.18 1.01 1.00

* * * * * * *

<

0 and high and 0

1.34 1.39 1.32 1.37 1.33 1.34 1.36 1.31 1.32 SED RR Total effect

as 1.10 1.11 1.06 1.10 1.08 1.09 1.10 1.06 1.06 >0 inchildhood >0 95%CI ------1.65 1.74 1.65 1.70 1.64 1.66 1.68 1.62 1.64

of standardized standardized of

exposed and non and exposed

. The analyses are adjusted for age and and age for areadjusted . Theanalyses socioeconomic disadvantage ( disadvantage socioeconomic Proportion mediated of the Total the of mediated Proportion ue to the mediating risk in adulthood. adulthood. in mediating risk to the ue parental SED and SEDand parental - exposed to high childhood childhood high to exposed effect 0.0 0.0 7.4 15 14 20 29 40 45 %

stand ardized ardized SED) SED) - ups. ups. This article isThis article by protected copyright. All rights reserved. Accepted Socioeconomic consortium. M;LIFEPATH VineisP, Kivimäki JP, Mackenbach SteptoeA, I, M, Kawachi Krogh V,Kelly M, Chadeau Bochud 7. Stringhin 2008;358:2468 NEngl Med. J countries. European in22 health in inequalities Health.Socioeconomic in Inequalities Socioeconomic Groupon Working 6. M Study. Finns Young OT. Raitakari M, Juonala Viikari JSA, Kähön N, Ahola M, Pitkänen Oikonen E, 5. Suomela resistance. with non associated is consumption meat processed red and Article4. Zelber exist of resolution the liver and Byrne CD. SH, Wild JY,Kim JY, S,Lee Ryu 3. Sung KC, disease. amultisystem G. NAFLD: Targher 2. ByrneCD, Association Gastroenterological American andthe Gastroenterology, AmericanCollege of Liver Diseases, of the Study non of and management K, EM, Cusi Brunt Diehl AM, Lavine JE, Z, N,Younossi 1. Chalasani REFERENCES ackenbach JP, Stirbu I, Roskam AJ, Schaap MM, Menvielle G, Leinsalu M, Kunst AE; European Union Union European AE; M,Kunst Leinsalu G, Menvielle MM, Schaap Roskam AJ, I, JP,Stirbu ackenbach en N, Kähönen M, Lehtimäki T, Taittonen L, Tossavainen P, Jula A, Loo BM, Mikkilä V, Telama R, Telama MikkiläV, BM, JulaA,Loo P, L,Tossavainen T,Taittonen M,Lehtimäki en N,Kähönen - Sagi S,Ivancovsky Sagi J Hepatol. 2018;68:1239 J i S, Carmeli C, Jokela M, Avendaño M, Muennig P, Guida F, Ricceri F, d'Errico A, Barros H, A,Barros F,d'Errico F,Ricceri Guida P, M, Muennig M,Avendaño Jokela Carmeli C, i S,

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