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Journal Article
Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes
2004
Overview
Genetic Variation Near the Hepatocyte Nuclear Factor-4α Gene Predicts Susceptibility to Type 2 Diabetes
Kaisa Silander 1 ,
Karen L. Mohlke 1 ,
Laura J. Scott 2 ,
Erin C. Peck 1 ,
Pablo Hollstein 1 ,
Andrew D. Skol 2 ,
Anne U. Jackson 2 ,
Panagiotis Deloukas 3 ,
Sarah Hunt 3 ,
George Stavrides 3 ,
Peter S. Chines 1 ,
Michael R. Erdos 1 ,
Narisu Narisu 1 ,
Karen N. Conneely 2 ,
Chun Li 2 ,
Tasha E. Fingerlin 2 ,
Sharanjeet K. Dhanjal 4 ,
Timo T. Valle 5 6 ,
Richard N. Bergman 7 ,
Jaakko Tuomilehto 5 6 8 ,
Richard M. Watanabe 4 ,
Michael Boehnke 2 and
Francis S. Collins 1
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
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
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 .
Accepted January 13, 2004.
Received September 10, 2003.
DIABETES
Publisher
American Diabetes Association
Subject
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/ Biological and medical sciences
/ Chromosomes, Human, Pair 20 - genetics
/ Diabetes Mellitus, Type 2 - blood
/ Diabetes Mellitus, Type 2 - genetics
/ Diabetes. Impaired glucose tolerance
/ Endocrine pancreas. Apud cells (diseases)
/ Etiopathogenesis. Screening. Investigations. Target tissue resistance
/ Family
/ Finland
/ Genetic Predisposition to Disease - genetics
/ Genomes
/ Genotype
/ Humans
/ Polymorphism, Single Nucleotide - genetics
