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

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

7 Citations (Scopus)

Abstract

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
JournalDiabetes
Volume55
Issue number6
Pages (from-to)1869-73
Number of pages5
ISSN0012-1797
DOIs
Publication statusPublished - 2006

Keywords

  • 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

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