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.