Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.
Soranzo N., Sanna S., Wheeler E., Gieger C., Radke D., Dupuis J., Bouatia-Naji N., Langenberg C., Prokopenko I., Stolerman E., Sandhu MS., Heeney MM., Devaney JM., Reilly MP., Ricketts SL., Stewart AFR., Voight BF., Willenborg C., Wright B., Altshuler D., Arking D., Balkau B., Barnes D., Boerwinkle E., Böhm B., Bonnefond A., Bonnycastle LL., Boomsma DI., Bornstein SR., Böttcher Y., Bumpstead S., Burnett-Miller MS., Campbell H., Cao A., Chambers J., Clark R., Collins FS., Coresh J., de Geus EJC., Dei M., Deloukas P., Döring A., Egan JM., Elosua R., Ferrucci L., Forouhi N., Fox CS., Franklin C., Franzosi MG., Gallina S., Goel A., Graessler J., Grallert H., Greinacher A., Hadley D., Hall A., Hamsten A., Hayward C., Heath S., Herder C., Homuth G., Hottenga J-J., Hunter-Merrill R., Illig T., Jackson AU., Jula A., Kleber M., Knouff CW., Kong A., Kooner J., Köttgen A., Kovacs P., Krohn K., Kühnel B., Kuusisto J., Laakso M., Lathrop M., Lecoeur C., Li M., Li M., Loos RJF., Luan J., Lyssenko V., Mägi R., Magnusson PKE., Mälarstig A., Mangino M., Martínez-Larrad MT., März W., McArdle WL., McPherson R., Meisinger C., Meitinger T., Melander O., Mohlke KL., Mooser VE., Morken MA., Narisu N., Nathan DM., Nauck M., O'Donnell C., Oexle K., Olla N., Pankow JS., Payne F., Peden JF., Pedersen NL., Peltonen L., Perola M., Polasek O., Porcu E., Rader DJ., Rathmann W., Ripatti S., Rocheleau G., Roden M., Rudan I., Salomaa V., Saxena R., Schlessinger D., Schunkert H., Schwarz P., Seedorf U., Selvin E., Serrano-Ríos M., Shrader P., Silveira A., Siscovick D., Song K., Spector TD., Stefansson K., Steinthorsdottir V., Strachan DP., Strawbridge R., Stumvoll M., Surakka I., Swift AJ., Tanaka T., Teumer A., Thorleifsson G., Thorsteinsdottir U., Tönjes A., Usala G., Vitart V., Völzke H., Wallaschofski H., Waterworth DM., Watkins H., Wichmann H-E., Wild SH., Willemsen G., Williams GH., Wilson JF., Winkelmann J., Wright AF., WTCCC None., Zabena C., Zhao JH., Epstein SE., Erdmann J., Hakonarson HH., Kathiresan S., Khaw K-T., Roberts R., Samani NJ., Fleming MD., Sladek R., Abecasis G., Boehnke M., Froguel P., Groop L., McCarthy MI., Kao WHL., Florez JC., Uda M., Wareham NJ., Barroso I., Meigs JB.
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).