A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes

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Jakob Ek, Sara P Hansen, Maria Lajer, Carine Nicot, Trine W Boesgaard, Stepanka Pruhova, Anders Johansen, Anders Albrechtsen, Knud Yderstraede, Jeannet Lauenborg, Marcelina Parrizas, Sylvia F Boj, Torben Jørgensen, Knut Borch-Johnsen, Peter Damm, Jorge Ferrer, Jan Lebl, Oluf Pedersen, Torben Hansen

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4 alpha gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A -192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the -192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P=0.004). Examination of the families showed that carriers of the -192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions -1107g/t and -858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.
Original languageEnglish
Issue number6
Pages (from-to)1869-73
Number of pages5
Publication statusPublished - 2006

    Research areas

  • Adult, Age Factors, Aged, Binding Sites, Blood Glucose, Body Mass Index, Diabetes Mellitus, Type 2, Electrophoretic Mobility Shift Assay, Female, Genotype, Haplotypes, Hepatocyte Nuclear Factor 4, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Protein Binding, Sex Factors

ID: 38455421