Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
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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, Stewart Alexandre F R, Voight Benjamin F, Willenborg Christina, Wright Benjamin, Altshuler David, Arking Dan, Balkau Beverley, Barnes Daniel, Boerwinkle Eric, Böhm Bernhard, Bonnefond Amélie, Bonnycastle Lori L, Boomsma Dorret I, Bornstein Stefan R, Böttcher Yvonne, Bumpstead Suzannah, Burnett-Miller Mary Susan, Campbell Harry, Cao Antonio, Chambers John, Clark Robert, Collins Francis S, Coresh Josef, de Geus Eco J C, Dei Mariano, Deloukas Panos, Döring Angela, Egan Josephine M, Elosua Roberto, Ferrucci Luigi, Forouhi Nita, Fox Caroline S, Franklin Christopher, Franzosi Maria Grazia, Gallina Sophie, Goel Anuj, Graessler Jürgen, Grallert Harald, Greinacher Andreas, Hadley David, Hall Alistair, Hamsten Anders, Hayward Caroline, Heath Simon, Herder Christian, Homuth Georg, Hottenga Jouke-Jan, Hunter-Merrill Rachel, Illig Thomas, Jackson Anne U, Jula Antti, Kleber Marcus, Knouff Christopher W, Kong Augustine, Kooner Jaspal, Köttgen Anna, Kovacs Peter, Krohn Knut, Kühnel Brigitte, Kuusisto Johanna, Laakso Markku, Lathrop Mark, Lecoeur Cécile, Li Man, Li Mingyao, Loos Ruth J F, Luan Jian'an, Lyssenko Valeriya, Mägi Reedik, Magnusson Patrik K E, Mälarstig Anders, Mangino Massimo, Martínez-Larrad María Teresa, März Winfried, McArdle Wendy L, McPherson Ruth, Meisinger Christa, Meitinger Thomas, Melander Olle, Mohlke Karen L, Mooser Vincent E, Morken Mario A, Narisu Narisu, Nathan David M, Nauck Matthias, O'Donnell Chris, Oexle Konrad, Olla Nazario, Pankow James S, Payne Felicity, Peden John F, Pedersen Nancy L, Peltonen Leena, Perola Markus, Polasek Ozren, Porcu Eleonora, Rader Daniel J, Rathmann Wolfgang, Ripatti Samuli, Rocheleau Ghislain, Roden Michael, Rudan Igor, Salomaa Veikko, Saxena Richa, Schlessinger David, Schunkert Heribert, Schwarz Peter, Seedorf Udo, Selvin Elizabeth, Serrano-Ríos Manuel, Shrader Peter, Silveira Angela, Siscovick David, Song Kjioung, Spector Timothy D, Stefansson Kari, Steinthorsdottir Valgerdur, Strachan David P, Strawbridge Rona, Stumvoll Michael, Surakka Ida, Swift Amy J, Tanaka Toshiko, Teumer Alexander, Thorleifsson Gudmar, Thorsteinsdottir Unnur, Tönjes Anke, Usala Gianluca, Vitart Veronique, Völzke Henry, Wallaschofski Henri, Waterworth Dawn M, Watkins Hugh, Wichmann H-Erich, Wild Sarah H, Willemsen Gonneke, Williams Gordon H, Wilson James F, Winkelmann Juliane, Wright Alan F, WTCCC, Zabena Carina, Zhao Jing Hua, Epstein Stephen E, Erdmann Jeanette, Hakonarson Hakon H, Kathiresan Sekar, Khaw Kay-Tee, Roberts Robert, Samani Nilesh J, Fleming Mark D, Sladek Robert, Abecasis Gonçalo, Boehnke Michael, Froguel Philippe, Groop Leif, McCarthy Mark I, Kao W H Linda, Florez Jose C, Uda Manuela, Wareham Nicholas J, Barroso Inês, Meigs James B
Аннотация
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).