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Single nucleotide polymorphisms of the HNF4α gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial

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Abstract

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4α, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D′>0.97, r 2>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09–2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.

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Acknowledgement

The STOP-NIDDM trial and DNA analysis were funded by an unrestricted grant from Bayer AG to M. L.

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Authors and Affiliations

  1. Department of Medicine, University of Kuopio, 70210, Kuopio, Finland

    Laura Andrulionytė, Olli Laukkanen & Markku Laakso

  2. Research Centre, Centre Hospitalier de l’Université de Montréal, Hôtel-Dieu, Department of Medicine, University of Montreal, Quebec, Canada

    Jean-Louis Chiasson

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  1. Laura Andrulionytė
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  2. Olli Laukkanen
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  3. Jean-Louis Chiasson
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  4. Markku Laakso
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STOP-NIDDM Study Group

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Correspondence to Markku Laakso.

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The first two authors contributed equally to this work.

Members are listed in a previous article published in the Lancet (2002 359: 2072–2077).

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Andrulionytė, L., Laukkanen, O., Chiasson, JL. et al. Single nucleotide polymorphisms of the HNF4α gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial. J Mol Med 84, 701–708 (2006). https://doi.org/10.1007/s00109-006-0063-3

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  • DOI: https://doi.org/10.1007/s00109-006-0063-3

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