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Soranzo, N.* ; Sanna, S.* ; Wheeler, E.* ; Gieger, C. ; Radke, D.* ; Dupuis, J. ; Boutaia-Naji, N.* ; Langenberg, C.* ; Prokopenko, I.* ; Stolerman, E.* ; Sandhu, M.S.* ; Heeney, M.M.* ; Devaney, J.M.* ; Reilly, M.P.* ; Ricketts, S.L.* ; Stewart, A.F.R.* ; Voight, B.F.* ; Willenborg, C.* ; Wright, B.* ; Altshuler, D.* ; Arking, D.* ; Balkau, B.* ; Barnes, D.* ; Boerwinkle, E. ; Bohm, B.* ; Bonnefond, A.* ; Bonnycastle, L.L.* ; Boomsma, D.I.* ; Bornstein, S.R.* ; Böttcher, Y.* ; Bumpstead, S.* ; Burnett-Miller, M.S.* ; Campbell, H.* ; Cao, A.* ; Chambers, J.* ; Clark, R.* ; Collins, F.S.* ; Coresh, J.* ; Geus, E.J.C.* ; Die, M.* ; Deloukas, P.* ; Döring, A.* ; Egan, J.M.* ; Elosua, R.* ; Ferrucci, L.* ; Forouhi, N.* ; Fox, C.S.* ; Franklin, C.* ; Franzosi, M.G.* ; Gallina, S.* ; Goel, A.* ; Graessler, J. ; Grallert, H. ; Greinacher, A.* ; Hadley, D.* ; Hall, A.* ; Hamsten, A.* ; Hayward, C.* ; Heath, S.* ; Herder, C.* ; Homuth, V.* ; Hottenga, J.-J.* ; Hunter-Merril, R.* ; Illig, T. ; Jackson, A.U.* ; Jula, A.* ; Kleber, M.* ; Knouff, C.W.* ; Kong, A.* ; Kooner, J.* ; Köttgen, A.* ; Kovacs, P.* ; Krohn, K.* ; Kühne, B.* ; Kuusisto, J.* ; Laakso, M.* ; Lecoeur, C.* ; Li, M.* ; Loos, R.J.F.* ; Luan, J.* ; Lyssenko, V.* ; Mägi, R.* ; Magnusson, P.K.E.* ; Mälastig, A.* ; Mangino, M. ; Martinez-Larrad, M.T.* ; Marz, W.* ; McArdle, W.L.* ; McPherson, R.* ; Meisinger, C. ; Meitinger, T. ; Melander, O.* ; Wichmann, H.-E. ; Winkelmann, J.* ; Peltonen, L. ; Rathmann, W. ; Wild, S.H. ; Procardis Consortium ; Wellcome Trust Case Consortium (WTCCC)

Common variants at 10 genomic loci influence hemoglobin A₁C levels via glycemic and nonglycemic pathways.

Diabetes 59, 3229-3239 (2010)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 HbA₁(c) 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 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c). CONCLUSIONS: GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). 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 HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).
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Publication type Article: Journal article
Document type Scientific Article
Keywords NONSPHEROCYTIC HEMOLYTIC-ANEMIA; FASTING GLUCOSE-LEVELS; TYPE-2 DIABETES RISK; GENETIC HEMOCHROMATOSIS; BLOOD-CELLS; ASSOCIATION; MTNR1B; RECLASSIFICATION; POLYMORPHISM; PREVALENCE
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