Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes
- Kaisa Silander1,
- Karen L. Mohlke1,
- Laura J. Scott2,
- Erin C. Peck1,
- Pablo Hollstein1,
- Andrew D. Skol2,
- Anne U. Jackson2,
- Panagiotis Deloukas3,
- Sarah Hunt3,
- George Stavrides3,
- Peter S. Chines1,
- Michael R. Erdos1,
- Narisu Narisu1,
- Karen N. Conneely2,
- Chun Li2,
- Tasha E. Fingerlin2,
- Sharanjeet K. Dhanjal4,
- Timo T. Valle56,
- Richard N. Bergman7,
- Jaakko Tuomilehto568,
- Richard M. Watanabe4,
- Michael Boehnke2 and
- Francis S. Collins1
- 1Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland
- 2Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
- 3The Wellcome Trust Sanger Institute, Hinxton, U.K
- 4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
- 5Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
- 6Department of Biochemistry, National Public Health Institute, Helsinki, Finland
- 7Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
- 8Department of Public Health, University of Helsinki, Helsinki, Finland
- Address correspondence and reprint requests to Michael Boehnke, PhD, Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029. E-mail: boehnke{at}umich.edu
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.
- ASP, affected sibling pair
- EC, elderly control
- FUSION, Finland-United States Investigation of NIDDM Genetics
- GIST, Genotype-Identity-By-Descent Sharing Test
- HNF, hepatocyte nuclear factor
- IBD, identity by descent
- LD, linkage disequilibrium
- LOD, logarithm of odds
- MLS, maximum LOD score
- MODY, maturity-onset diabetes of the young
- OGTT, oral glucose tolerance test
- SNP, single nucleotide polymorphism
Footnotes
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K.S. and K.L.M. contributed equally to this work.
The current affiliation for K.S. is with the Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. The current affiliation for C.L. is with the Department of Molecular Physiology and Biophysics, Program in Human Genetics, Vanderbilt University, Nashville, Tennessee.
Posted on the World Wide Web at http://diabetes.diabetesjournals.org on 9 March 2004.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
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- Accepted January 13, 2004.
- Received September 10, 2003.
- DIABETES
