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Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.

Original publication




Journal article



Publication Date





3002 - 3006


Adult, Age of Onset, Chromosomes, Human, Pair 20, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Female, Genetic Carrier Screening, Genetic Variation, Genotype, Hepatocyte Nuclear Factor 4, Humans, Linkage Disequilibrium, Male, Middle Aged, Phosphoproteins, Promoter Regions, Genetic, Reference Values, Transcription Factors, United Kingdom