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- Title
Common Variants at 10 Genomic Loci Influence Hemoglobin A<sub>1C</sub> Levels via Glycemic and Nonglycemic Pathways.
- Authors
Soranzo, Nicole; Sanna, Serena; Wheeler, Eleanor; Gieger, Christian; Radke, Dörte; Dupuis, Josée; Bouatia-Naji, Nabila; Langenberg, Claudia; Prokopenko, Inga; Stolerman, Elliot; Sandhu, Manjinder S.; Heeney, Matthew M.; Devaney, Joseph M.; Reilly, Muredach P.; Ricketts, Sally L.
- Abstract
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]), MTNR1B (rs1387153/P = 4.0 X 10[sup -11]), 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
- Publication
Diabetes, 2010, Vol 59, Issue 12, p3229
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db10-0502