A prevalent amino acid polymorphism at codon 98 in the hepatocyte nuclear factor-1alpha gene is associated with reduced serum C-peptide and insulin responses to an oral glucose challenge.

Abstract

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause the type 3 form of maturity-onset diabetes of the young (MODY3), which is characterized by a severe impairment of insulin secretion. In addition to disease-associated mutations, three common amino acid polymorphisms have been identified in the HNF-1alpha gene: Ile/Leu27, Ala/Val 98, and Ser/Asn487. We have addressed the question of whether these variants of the HNF-1alpha gene are associated with altered glucose-induced C-peptide and insulin responses or late-onset NIDDM. Among 245 NIDDM patients, the allelic frequency of the Val 98 variant was 3.7% (95% CI 2.0-5.4%) vs. 4.4% (2.6-6.2%) among 240 glucose tolerant control subjects (NS). Studies of genotype-phenotype interactions in 240 middle-aged control subjects showed, however, that heterozygous subjects (i.e., genotype Ala/Val 98) had an 18% decrease in 30-min serum C-peptide level (P = 0.004) as well as a 23% decrease in 30-min serum insulin level (P = 0.03) during an oral glucose tolerance test. One Val 98 homozygote subject had a more severe reduction in stimulated insulin and C-peptide levels. The impact of the homozygous carrier status was similar in a study of 377 healthy young subjects. In contrast, the Ile/Leu27 and Ser/Asn487 polymorphisms were not associated with altered C-peptide and insulin release or NIDDM. In conclusion, 8% of white subjects of Danish ancestry are heterozygous for the Ala/Val 98 polymorphism in the HNF-1alpha gene, which in middle-aged subjects is associated with a approximately 20% reduction in serum C-peptide and insulin responses 30 min after an oral glucose challenge. Val 98 homozygotes may exhibit a more severe defect in the early glucose-induced insulin response.