A PREVALENT AMINO-ACID POLYMORPHISM AT CODON-98 IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE IS ASSOCIATED WITH REDUCED SERUM C-PEPTIDE AND INSULIN RESPONSES TO AN ORAL GLUCOSE CHALLENGE

Mutations in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene cause the type 3 form of maturity-onset diabetes of the young (MODY3), which is characterized by a severe impairment of insulin secretion. I n addition to disease-associated mutations, three common amino acid po lymorphisms have been identified in the HNF-1 alpha gene: Ile/Leu27, A la/Val98, and Ser/Asn487. We have addressed the question of whether th ese variants of the HNF-1 alpha gene are associated with altered gluco se-induced C-peptide and insulin responses or late-onset NIDDM. Among 245 NIDDM patients, the allelic frequency of the Val98 variant was 3.7 % (95% CI 2.0-5.4%) vs. 4.4% (2.6-6.2%) among 240 glucose tolerant con trol subjects (NS). Studies of genotype-phenotype interactions in 240 middle-aged control subjects showed, however, that heterozygous subjec ts (i.e., genotype Ala/Val98) had an 18% decrease in 30-min serum C-pe ptide level (P = 0.004) as well as a 23% decrease in 30-min serum insu lin level (P = 0.03) during an oral glucose tolerance test. One Val98 homozygote subject had a more severe reduction in stimulated insulin a nd C-peptide levels. The impact of the homozygous carrier status was s imilar 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 subje cts of Danish ancestry are heterozygous for the Ala/Val98 polymorphism in the HNF-1 alpha gene, which in middle-aged subjects is associated with a similar to 20% reduction in serum C-peptide and insulin respons es 30 min after an oral glucose challenge. Val98 homozygotes may exhib it a more severe defect in the early glucose-induced insulin response.