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Impact of Glucose Level on Micro- and Macrovascular Disease in The Diabetes Care 1 Impact of Glucose Level on Micro- Frida Emanuelsson,1,2,3 Sarah Marott,1,2,3 Anne Tybjærg-Hansen,1,2,3,4 and Macrovascular Disease in the Børge G. Nordestgaard,2,3,4,5 and Marianne Benn1,2,3 General Population: A Mendelian Randomization Study https://doi.org/10.2337/dc19-1850 OBJECTIVE To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population. RESEARCH DESIGN AND METHODS This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 1Department of Clinical Biochemistry, Rigshospi- CARDIOVASCULAR AND METABOLIC RISK from the CKDGen Consortium, and 452,264 from the UK Biobank. talet, Copenhagen University Hospital, Copenha- gen, Denmark 2 RESULTS Faculty of Health and Medical Sciences, Univer- sity of Copenhagen, Copenhagen, Denmark Observationally, glucose levels in the normoglycemic range and higher were as- 3TheCopenhagenGeneralPopulationStudy,Herlev sociatedwith high risksof retinopathy, neuropathy,diabetic nephropathy, PAD,and and Gentofte Hospital, Copenhagen University P < Hospital, Herlev, Denmark MI (all for trend 0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L 4 – – The Copenhagen City Heart Study, Frederiksberg higher glucose level was 2.01 (95% CI 1.18 3.41) for retinopathy, 2.15 (1.38 3.35) for and Bispebjerg Hospital, Copenhagen University neuropathy, 1.58 (1.04–2.40) for diabetic nephropathy, 0.97 (0.84–1.12) for esti- Hospital, Frederiksberg, Denmark mated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90–1.58) for 5Department of Clinical Biochemistry, Herlev PAD, and 1.49 (1.02–2.17) for MI. Summary-level data from the MAGIC, the CKDGen and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26–9.15) – – Corresponding author: Marianne Benn, marianne for retinopathy, 1.48 (0.83 2.66) for peripheral neuropathy, 0.98 (0.94 1.01) for [email protected] eGFR <60 mL/min/1.73 m2, and 1.23 (0.57–2.67) for PAD per 1 mmol/L higher Received 17 September 2019 and accepted 23 glucose level. January 2020 This article contains Supplementary Data online CONCLUSIONS at http://care.diabetesjournals.org/lookup/suppl/ Glucose levels in the normoglycemic range and higher were prospectively asso- doi:10.2337/dc19-1850/-/DC1. ciated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR © 2020 by the American Diabetes Association. <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in ge- Readers may use this article as long as the work is properly cited, the use is educational and not for netic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, fi fi < pro t, and the work is not altered. More infor- but they could not be con rmed for PAD and seemed to be refuted for eGFR 60 mation is available at https://www.diabetesjournals 2 mL/min/1.73 m . .org/content/license. Diabetes Care Publish Ahead of Print, published online February 13, 2020 2 Impact of Glucose Level on Vascular Disease Diabetes Care High glucose levels are observationally glucose levels (1,9,10); thus, second, we were used in order to genotype seven and causally associated with a high risk of tested whether they also did so in our variants of the genes GCP62/ABCB1 ischemic heart disease in individuals with populations. Third, we tested whether (rs560887), GCK (rs4607517), DGKB and those without diabetes (1,2). Simi- the genetic variants associated with high (rs2191349), ADCY5 (rs11708067), CDKN2A/ larly, hyperglycemia is a well-known risk glucose levels also associated, as an in- B (rs10811661 and rs2383206), and TCF7L2 factor for microvascular disease in indi- dication of causality, with risk of disease. (rs7903146), which have been shown to viduals with diabetes, and treatment with Fourth, we analyzed instrumental varia- be associated with high glucose levels glucose-lowering drugs reduces the risk bles to obtain causal risk estimates per (1,9,10). The variants were combined into of microvascular complications in such 1 mmol/L (18 mg/dL) higher glucose a weighted allele score, which accounted individuals (3,4). Whether high glucose levels. Fifth and last, we validated our for the effect of each allele on random levels increase the risk of a spectrum of results using a two-sample MR design plasma glucose and the frequency of peripheral micro- and macrovascular dis- with summary-level data based on 26 ge- each allele in the CCHS and CGPS pop- eases in the general population, and netic variants associated with fasting glu- ulations (16). In order to compare the whether the magnitude of such risk varies cose levels in individuals without diabetes effect of the same genetic variants on between vascular compartments, is less from the Meta-Analyses of Glucose and fastingglucoselevels, theallele scorewas clear. Also uncertain is whether the ef- Insulin-RelatedTraitsConsortium(MAGIC), also weighted on the basis of its effect on fect of glucose-lowering drugs on vascu- and end point data from the UK Biobank fasting glucose levels in MAGIC partic- lar disease is caused by glucose lowering and the CKDGen Consortium (11–14). ipants. The weighted allele scores were per se or whether other mechanisms also divided into five categories, cut at the are involved, as most glucose-lowering RESEARCH DESIGN AND METHODS 25th, 50th, 75th, and 95th percentiles, in fl drugs have pleiotropic effects, including Study Population order to re ect stepwise increases in glu- improvements in concomitant obesity, We included 117,193 individuals from cose levels from below the median to hyperlipidemia, and hypertension (5,6). two similar studies of the Danish general extremely high values. In order to determine whether a risk population: the CCHS and the CGPS (1). factor is causally related to a disease, Participants were white and of Danish End Points several lines of evidence should be con- descent, and none were included in more End points were based on diagnoses of sidered, including mechanistic studies, lon- than one study. For detailed descrip- retinopathy, peripheral neuropathy, di- gitudinal epidemiological studies, genetic tions of the cohorts, see Supplementary abetic nephropathy, PAD, and MI accord- Mendelian randomization (MR) studies, Appendix 1. Both studies were approved ing to the codes from the World Health and randomized controlled trials (7,8). by institutional boards at Herlev and Gen- Organization’s ICD-8 and ICD-10. (For spe- MR is an epidemiological approach to tofte Hospitals and The Danish National cific ICD codes, see Supplementary Table assessing causality that uses the random Committee on Health Research Ethics, 1.) Relevant data were collected from assortment of alleles at conception to Copenhagen, Denmark (KF-100.2039/91, 1 January 1977 through 10 April 2018 largely circumvent confounding and re- KF-01–144/01, H-KF-01–144/01), and they by reviewing diagnoses from all hospital verse causation (8). Applying the princi- were conducted according to the Declara- admissions and outpatient clinic visits in ples of MR in a general population, we tion of Helsinki. Written informed consent the national Danish Patient Registry and tested the hypothesis that high glucose was obtained from all individuals. the national Danish Registry of Causes of levels within the normal range and higher Death. CKD was defined as an estimated causally associate with high risks of ret- Plasma Glucose glomerular filtration rate (eGFR) ,60 inopathy, peripheral neuropathy, and Nonfasting plasma glucose was measured mL/min/1.73 m2, corresponding to the diabetic nephropathy, representing mi- by using a colorimetric assay (Konelab; KDIGO definition of mildly to moderately crovascular disease, or with high risks of Boehringer, Mannheim, Germany). Blood decreased (stage G3) kidney function or chronic kidney disease (CKD) and periph- samples were taken at random, irrespective worse (17). eGFR was calculated from eral arterial disease (PAD), representing a of time since and content of the last meal. creatinine by using the CKD-EPI creati- mix of micro- and macrovascular PAD. Time (hours) since the last meal was self- nine equation (18). For detailed descrip- Myocardial infarction (MI) was included reported. In order to examine the observa- tions of end points and covariates, see as a positive control for the genetic in- tional association between glucose levels Supplementary Appendix 2. strument, that is, as a confirmation of the and disease, individuals without diabetes association between the genetic instru- were categorized, on the basis of glucose Statistical Analyses ment and the risk of MI. level at baseline, into five groups that reflect We used Stata SE 14.2 to analyze the data. In two cohorts from the Danish general stepwise increases in glucose level, ranging Deviation from Hardy-Weinberg equilib- populationdparticipants in the Copen- from $4.0 mmol/L to above the diabetes rium was tested by using the Pearson hagen City Heart Study (CCHS) and those threshold of 11.1 mmol/L (15). Individuals x2 test. To test for trend across ordered in the Copenhagen General Population with levels between 4.0 and 5.4 mmol/L categories of glucose levels, genotypes, Study (CGPS)dwe first tested whether were defined as the reference group. and weighted allele scores, we used random plasma glucose levels at baseline the nonparametric Cuzick extension of a were prospectively associated with risk of Genotypes Wilcoxon rank sum test.
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