Common variants at 10 genomic loci influence hemoglobin [A.sub.1C] levels via glycemic and nonglycemic pathways

OBJECTIVE--Glycated hemoglobin ([HbA.sub.1c]), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of [HbA.sub.1c]. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on [HbA.sub.1c] levels. RESEARCH DESIGN AND METHODS--We studied associations with [HbA.sub.1c] in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of [HbA.sub.1c] loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS--Ten loci reached genome-wide significant association with [HbA.sub.1c], including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x [10.sup.-26]), HFE (rs1800562/P = 2.6 x [10.sup.-20]), TMPRSS6 (rs855791/P = 2.7 x [10.sup.-14]), ANK1 (rs4737009/ P = 6.1 x [10.sup.-12] ), SPTA1 (rs2779116/P = 2.8 x [10.sup.-9]) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x [10.sup.-9]), and four known [HbA.sub.1c] loci: HK1 (rs16926246/P = 3.1 x [10.sup.-54]), MTNRIB (rs1387153/P = 4.0 x 10-n), GCK (rs1799884/P = 1.5 x [10.sup.-20]) and G6PC2/ABCB11 (rs552976/P = 8.2 x [10.sup.-18]). We show that associations with [HbA.sub.1c] are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% [HbA.sub.1c]) difference between the extreme 10% tails of the risk score, and would reclassify ~2% of a general white population screened for diabetes with [HbA.sub.1c]. CONCLUSIONS--GWAS identified 10 genetic loci reproducibly associated with [HbA.sub.1c]. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence [HbA.sub.1c] levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by [HbA.sub.1c]. Diabetes 59: 3229-3239, 2010