Association Testing of Variants in the Hepatocyte Nuclear Factor 4α Gene With Risk of Type 2 Diabetes in 7,883 People
- Wendy Winckler123,
- Robert R. Graham123,
- Paul I.W. de Bakker123,
- Maria Sun13,
- Peter Almgren4,
- Tiinamaija Tuomi5,
- Daniel Gaudet6,
- Thomas J. Hudson7,
- Kristin G. Ardlie8,
- Mark J. Daly3,
- Joel N. Hirschhorn239,
- Leif Groop4 and
- David Altshuler1231011
- 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
- 2Department of Genetics, Harvard Medical School, Boston, Massachusetts
- 3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- 4Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
- 5Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
- 6University of Montreal Community Genomic Center, Chicoutimi Hospital, Montreal, Quebec, Canada
- 7McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
- 8Genomics Collaborative, Inc., Cambridge, Massachusetts
- 9Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
- 10Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
- 11Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Address correspondence and reprint requests to David Altshuler, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu. Or Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}endo.mas.lu.se
Abstract
Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4α (HNF4α) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4α coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4α. Although our combined results fail to replicate the previously reported association of common variants in HNF4α with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
- CEPH, Centre d’Etude du Polymorphisme Humain
- GCI, Genomics Collaborative, Inc
- HNF4α, hepatocyte nuclear factor-4α
- LD, linkage disequilibrium
- MODY, maturity-onset diabetes of the young
- SNP, single nucleotide polymorphism
Footnotes
-
L.G. and D.A. jointly supervised the project.
J.N.H. is a member of an advisory board for and has received consulting fees from Correlagen. D.A. is a member of an advisory board for and has received consulting fees from Genomics Collaborative, Inc.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
-
- Accepted November 29, 2004.
- Received July 14, 2004.
- DIABETES
