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Diabetes. 2019 Jan 23. pii: db180573. doi: 10.2337/db18-0573. [Epub ahead of print]

Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes.

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Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, 00290, Helsinki, Finland.
Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, 00290, Helsinki, Finland.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland.
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Division of Endocrinology and Diabetes, Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, California, USA.
Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Medicine, Division of Endocrinology and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Department of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN, USA.
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
The Chronic Disease Prevention Unit, National Institute for Health and Welfare, 00271, Helsinki, Finland.


Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors, both in people with and without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes cohort, FinnDiane. Top results were examined for replication in type 1 diabetes cohorts DCCT/EDIC, WESDR, CACTI, EDC and RASS and a meta-analysis was performed. Three SNPs in high LD on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P<5×10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P<5×10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in a non-diabetic East Asian population (P≤0.013). A weighted genetic risk score created from 55 HbA1c associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetic complications.


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