Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes

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 × 10(−8)). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA(1c) 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 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.