Variants in the hepatocyte nuclear factor-1α and -4α genes in Finnish and Chinese subjects with late-onset type 2 diabetes

Abstract

OBJECTIVE - To determine the role of the hepatocyte nuclear factor (HNF)-1α and HNF-4α genes in the etiology of late-onset type 2 diabetes in Finnish and Chinese subjects. RESEARCH DESIGN AND METHODS - The whole coding regions of the genes encoding for HNF-1α and HNF-4α, including ~800 bp of the HNF-1α promoter, were investigated in 40 Finnish subjects (fasting C-peptide 50-570 pmol/1) and 47 Chinese subjects with type 2 diabetes by single-strand conformation polymorphism (SSCP) analysis. Frequencies of the variants of these genes were analyzed by restriction fragment-length polymorphism analysis in additional samples of 100 Finnish diabetic patients and 82 Finnish control subjects and in 58 Chinese diabetic patients and 51 Chinese control subjects. RESULTS - No previously reported gene defects were detected, but one novel functionally silent GCC→GCG variant (nucleotide 73, exon 10) was observed in the HNF-4α gene in a Chinese diabetic patient. Interestingly, the Ala98Val substitution of the HNF-1α gene occurred at a significantly higher frequency in 140 Finnish diabetic patients compared with 82 control subjects (P = 0.014). The Ala98Val variant was not, however, associated with abnormalities in insulin secretion evaluated by oral and intravenous glucose tolerance tests in subjects with normal (n = 295) or impaired (n = 38) glucose tolerance. CONCLUSIONS - Variants in the HNF-1α and HNF-4α genes are unlikely to play a major role in the pathogenesis of late-onset type 2 diabetes in Finnish and Chinese subjects. However, the association of the Ala98Val variant of the HNF-1α gene with type 2 diabetes in Finnish subjects may indicate a diabetogenic locus close to the HNF-1α gene.