Rare variants identified in the HNF-4α β-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes

Aims/hypothesis. The recently identified alternative promoter (P2) of HNF-4alpha is the major HNF-4alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility. Methods. To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4alpha. Results. Two variants were found that were not present in the control subjects. The -79C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79C/T or -276G/T single nucleotide substitutions. Conclusion/interpretation. We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.