Glycated hemoglobin (HbA 1c ) is an important measure of glycemia in diabetes. HbA 1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA 1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA 1c in FinnDiane at genome-wide significance (P < 5 3 10 28 ). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA 1c also in the meta-analysis with RASS (P < 5 3 10 28 ), where these variants had minor allele frequencies ‡1%. Furthermore, these SNPs were associated with HbA 1c in an East Asian population without diabetes (P £ 0.013). A weighted genetic risk score created from 55 HbA 1c -associated variants from the literature was associated with HbA 1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA 1c may lead to better prevention of diabetes complications.
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Acknowledgments. The authors thank the staff and all participants in the FinnDiane, DCCT/EDIC, CACTI, EDC, RASS, and WESDR study cohorts. Data on glycemic traits have been contributed by MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) investigators and have been downloaded from www.magicinvestigators.org. Funding. The FinnDiane Study and the work reported here were supported by grants from the Folkhälsan Research Foundation, Wilhelm och Else Stockmann Foundation, Novo Nordisk Foundation, Liv och Hälsa Society, Helsinki University Central Hospital Research Funds (EVO) and Academy of Finland (299200 and 275614), European Foundation for the Study of Diabetes (to N.S.), and the Orion Research Foundation (to A.S.). JDRF supported the genotyping of the FinnDiane subjects (grant 17-2013-7). CACTI was performed at the Barbara Davis Center for Childhood Diabetes in Denver, CO; the Colorado Heart Imaging Center in Denver, CO; and the University of Colorado Hospital. Support for CACTI was provided by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), grants R01-HL-61753, R01-HL-079611, and HL-113029, and JDRF grants 17-2013-313 and 17-2013-9. The study was performed at the Clinical Translational Research Center at the University of Colorado Denver supported by NIH M01-RR-000051 and NIH/National Center for Advancing Translational Sciences Colorado CTSA grant UL1-TR-001082. RASS was partly supported by research grants from the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (DK-51975), and the Canadian Institutes of Health Research (DCT 14281). RASS was also supported in part by a grant from the National Center for Research Resources of the NIH to the University of Minnesota General Clinical Research Center (M01-RR00400). WESDR was supported by grants from Research to Prevent Blindness and by National Eye Institute grant EY016378 (B.E.K.K. and R.K.). Duality of Interest. RASS was partly supported by research grants from Merck (in the U.S.) and Merck Frosst (in Canada). P.-H.G. has received investigator-initiated research grants from Eli Lilly and Roche; is an advisory board member for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Med-scape, Merck Sharp & Dohme (MSD), Mundipharma, Nestle, Novartis, Novo Nordisk, and Sanofi; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, MSD, Medscape, Novartis, Novo Nordisk, PeerVoice, and Sanofi. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.S. contributed to study design, researched FinnDiane data, performed meta-analysis, and wrote and edited the manuscript. N.S. prepared genotype data, contributed to study design, and wrote and reviewed the manuscript. J.C. prepared and analyzed data from the T1D replication cohorts. I.T. prepared the genotype data, contributed to data analysis, and reviewed the manuscript. D.M.M. and M.J.R. contributed to the CACTI study. J.K.S.-B. contributed to the CACTI study and reviewed the manuscript. T.C. contributed to the EDC study and reviewed and edited the manuscript. T.J.O. contributed to the EDC study and reviewed the manuscript. M.L.C. and M.M. contributed to RASS and reviewed the manuscript. B.E.K.K. and R.K. contributed to the WESDR study and reviewed the manuscript. E.V. reviewed the manuscript. M.P. contributed to the genome-wide genotyping and TaqMan SNP genotyping. C.F. and V.H. contributed to the collection of clinical data (FinnDiane) and reviewed the manuscript. A.D.P. contributed to study design and reviewed and edited the manuscript. P.-H.G. contributed to study design and reviewed and edited the manuscript. P.-H.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 54th Annual Meeting of the European Association for the Study of Diabetes, Berlin, Germany, 1–5 October 2018.