Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes
Author:
Silander Kaisa1, Mohlke Karen L.1, Scott Laura J.2, Peck Erin C.1, Hollstein Pablo1, Skol Andrew D.2, Jackson Anne U.2, Deloukas Panagiotis3, Hunt Sarah3, Stavrides George3, Chines Peter S.1, Erdos Michael R.1, Narisu Narisu1, Conneely Karen N.2, Li Chun2, Fingerlin Tasha E.2, Dhanjal Sharanjeet K.4, Valle Timo T.56, Bergman Richard N.7, Tuomilehto Jaakko568, Watanabe Richard M.4, Boehnke Michael2, Collins Francis S.1
Affiliation:
1. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 2. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 3. The Wellcome Trust Sanger Institute, Hinxton, U.K 4. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 5. Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 6. Department of Biochemistry, National Public Health Institute, Helsinki, Finland 7. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 8. Department of Public Health, University of Helsinki, Helsinki, Finland
Abstract
The Finland-United States Investigation Of NIDDM Genetics (FUSION) study aims to identify genetic variants that predispose to type 2 diabetes by studying affected sibling pair families from Finland. Chromosome 20 showed our strongest initial evidence for linkage. It currently has a maximum logarithm of odds (LOD) score of 2.48 at 70 cM in a set of 495 families. In this study, we searched for diabetes susceptibility variant(s) at 20q13 by genotyping single nucleotide polymorphism (SNP) markers in case and control DNA pools. Of 291 SNPs successfully typed in a 7.5-Mb interval, the strongest association confirmed by individual genotyping was with SNP rs2144908, located 1.3 kb downstream of the primary β-cell promoter P2 of hepatocyte nuclear factor-4α (HNF4A). This SNP showed association with diabetes disease status (odds ratio [OR] 1.33, 95% CI 1.06–1.65, P = 0.011) and with several diabetes-related traits. Most of the evidence for linkage at 20q13 could be attributed to the families carrying the risk allele. We subsequently found nine additional associated SNPs spanning a 64-kb region, including the P2 and P1 promoters and exons 1–3. Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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