J Mol Med (2006) 84: 701–708 DOI 10.1007/s00109-006-0063-3 ORIGINAL ARTICLE Laura Andrulionytė . Olli Laukkanen . Jean-Louis Chiasson . Markku Laakso . STOP-NIDDM Study Group Single nucleotide polymorphisms of the HNF4α gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial Received: 4 November 2005 / Accepted: 22 February 2006 / Published online: 13 July 2006 # Springer-Verlag 2006 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. Keywords Hepatocyte nuclear factor 4α . Single nucleotide polymorphism . Impaired glucose tolerance . Type 2 diabetes mellitus . STOP-NIDDM trial Introduction Hepatocyte nuclear factor 4α (HNF4α), a transcription factor of the nuclear hormone receptor superfamily, mainly expressed in liver, intestine, pancreatic islets, and kidney, is essential to hepatocyte differentiation and liver function [1]. Interacting with peroxisome proliferator-activated LAURA ANDRULIONYTE received her medical degree in the University of Vilnius, Lithuania. She is presently a Ph.D. student at the Department of Medicine, University of Kuopio. Her research focuses on the genetics of insulin resistance and type 2 diabetes mellitus. MARKKU LAAKSO received his medical degree and doctorate in internal medi- cine from the University of Kuopio, Finland. He is pre- sently Academy Professor at the Academy of Finland. His re- search interests include insulin resistance, genetics of type 2 diabetes mellitus, and cardio- vascular complications of type 2 diabetes mellitus. Ė The first two authors contributed equally to this work. Members are listed in a previous article published in the Lancet (2002 359: 2072–2077). L. Andrulionyte ˙ . O. Laukkanen . M. Laakso (*) Department of Medicine, University of Kuopio, 70210 Kuopio, Finland e-mail: markku.laakso@kuh.fi Tel.: +358-17-172151 Fax: +358-17-173993 J.-L. Chiasson Research Centre, Centre Hospitalier de l’Université de Montréal, Hôtel-Dieu, Department of Medicine, University of Montreal, Quebec, Canada