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

OBJECTIVE: Glycated hemoglobin (HbA1c), 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 HbA1c. We aimed to iden...

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Veröffentlicht in:Diabetes (New York, N.Y.) Jg. 59; H. 12; S. 3229 - 3239
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Alexandria, VA American Diabetes Association 01.12.2010
Schlagworte:
Biological and medical sciences
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Life Sciences
Medical sciences
Pharmacology and Therapeutics
Endocrinopathy
Variant
Hemoglobin A1c
Diabetes mellitus
ISSN:0012-1797, 1939-327X
Online-Zugang:Volltext
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Zusammenfassung:OBJECTIVE: Glycated hemoglobin (HbA1c), 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 HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS: We studied associations with HbA1c 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 HbA1c 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 HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10-26), HFE (rs1800562/P = 2.6 x 10-20), TMPRSS6 (rs855791/P = 2.7 x 10-14), ANK1 (rs4737009/P = 6.1 x 10-12), SPTA1 (rs2779116/P = 2.8 x 10-9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10-9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 x 10-54), MTNR1B (rs1387153/P = 4.0 x 10-11), GCK (rs1799884/P = 1.5 x 10-20) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10-18). We show that associations with HbA1c 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 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS: GWAS identified 10 genetic loci reproducibly associated with HbA1c. 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 HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c.
Bibliographie:ObjectType-Article-2
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PMCID: PMC2992787
The entire author list is available in the appendix, and the authors' institutional affiliations are available in the online appendix at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0502/DC1.
N.S., S.S., E.W., C.G., and D.R. contributed equally to this study.
ISSN:0012-1797
1939-327X
DOI:10.2337/db10-0502