Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways

作者：Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia‐Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S. Sandhu, Matthew M. Heeney, Joseph M. Devaney, Muredach P. Reilly, Sally L. Ricketts · 发表于：Diabetes · 年份：2010 · DOI：10.2337/db10-0502 · 被引用次数：474 · 研究领域：Genetic Associations and Epidemiology、Diabetes, Cardiovascular Risks, and Lipoproteins、Pancreatic function and diabetes

OBJECTIVE: Glycated hemoglobin (HbA₁(c)), 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 HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels. RESEARCH DESIGN AND METHODS: We studied associations with HbA₁(c) 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 HbA₁(c) 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(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with Hb...