Studies in 3,523 Norwegians and Meta-Analysis in 11,571 Subjects Indicate That Variants in the Hepatocyte Nuclear Factor 4α (HNF4A) P2 Region Are Associated With Type 2 Diabetes in Scandinavians

  1. Stefan Johansson12,
  2. Helge Ræder13,
  3. Stig Å Eide12,
  4. Kristian Midthjell4,
  5. Kristian Hveem4,
  6. Oddmund Søvik1,
  7. Anders Molven56 and
  8. Pål Rasmus Njølstad13
  1. 1Department of Clinical Medicine, University of Bergen, Bergen, Norway
  2. 2Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  3. 3Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  4. 4HUNT Research Center, Department of Public Health and General Practice, Norwegian University of Science and Technology, Verdal, Norway
  5. 5Gade Institute, University of Bergen, Norway
  6. 6Department of Pathology, Haukeland University Hospital, Bergen, Norway
  1. Address correspondence and reprint requests to Dr. Pål R. Njølstad, Department of Pediatrics, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: pal.njolstad{at}uib.no

Abstract

OBJECTIVE— Recent publications have found an association between common variants near the hepatocyte nuclear factor 4α (HNF4A) P2 promoter and type 2 diabetes in some populations but not in others, and the role for HNF4A in type 2 diabetes has remained unclear. In an attempt to address these inconsistencies, we investigated HNF4A single nucleotide polymorphisms (SNPs) in a large population-based sample and included a meta-analysis of published studies.

RESEARCH DESIGN AND METHODS— We genotyped 12 SNPs in the HNF4A region in a Norwegian population–based sample of 1,644 individuals with type 2 diabetes and 1,879 control subjects (the Nord-Trøndelag Health Study [HUNT] 2). We combined our data with all previously published case/control studies and performed a meta-analysis.

RESULTS— Consistent with initial studies, we found a trend toward association for the SNPs rs1884613 (odds ratio [OR] 1.17 [95% CI 1.03–1.35]) and rs2144908 (1.21 [1.05–1.38]) in the P2 region and for rs4812831 (1.21 [1.02–1.44]), located 34 kb downstream of the P2 promoter. Meta-analysis, comprising 12,292 type 2 diabetic case and 15,519 control subjects, revealed a nonsignificant OR of 1.05 (95% CI 0.98–1.12) but with significant heterogeneity between the populations. We therefore performed a subanalysis including only the data for subjects from Scandinavia. Among the 4,000 case and 7,571 control Scandinavian subjects, a pooled OR of 1.14 (1.06–1.23), P = 0.0004, was found for the SNP rs1884613.

CONCLUSIONS— Our results suggest that variation in the HNF4A region is associated with type 2 diabetes in Scandinavians, highlighting the importance of exploring small genetic effects in large, homogenous populations.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 7 September 2007. DOI: 10.2337/db07-0513.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0513.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted September 4, 2007.
    • Received April 12, 2007.
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  1. Published online before print September 7, 2007, doi: 10.2337/db07-0513 Diabetes December 2007 vol. 56 no. 12 3112-3117
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