A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry

Diabetes. 2006 Jun;55(6):1899-903. doi: 10.2337/db05-1677.

Abstract

Variants in hepatocyte nuclear factor (HNF)-4alpha cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Animals
  • Cell Line, Tumor
  • Denmark
  • Diabetes Mellitus, Type 2 / genetics*
  • Exons
  • Genetic Vectors / genetics
  • Haplotypes*
  • Hepatocyte Nuclear Factor 4 / genetics*
  • Humans
  • Introns
  • Middle Aged
  • Norway
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics*
  • Registries
  • Transfection
  • White People / genetics*

Substances

  • Hepatocyte Nuclear Factor 4