GLUCOKINASE GENE VARIATIONS IN JAPANESE-AMERICANS WITH A FAMILY HISTORY OF NIDDM

OBJECTIVE - To determine if sequence variants in the glucokinase (GCK) gene contribute to the high risk of impaired glucose metabolism in Ja panese-Americans and whether the gene sequence differs between Japanes e-Americans and Caucasians. RESEARCH DESIGN AND METHODS - Forty-seven unrelated Japanese-Americans with one or more first-degree relatives w ith non-insulin-dependent diabetes mellitus (NIDDM) were selected, irr espective of glucose tolerance status. By World Health Organization cr iteria, 13 had normal glucose tolerance, 11 had impaired glucose toler ance, and 23 had NIDDM. Variations in the GCK gene were identified by single-strand conformation polymorphism analysis and sequenced using s tandard techniques. RESULTS - Six variants of the GCK gene were identi fied in a total of 21 subjects: 1) a G-->A substitution at nucleotide -30 in the beta-cell-specific promoter; 2) an A-->G substitution at nu cleotide 244 in the 5'-untranslated region (5'-UTR) of exon 1a; 3) a C -->G substitution at nucleotide 403 in the 5'-UTR of exon 1a; 4) a G-- A variant 13 base pair (bp) 5' to the intron 3 exon 4 junction; 5) a s ilent substitution in the third base of codon 145 in exon 4; and 6) a C-->T substitution 8 bp 3' to the exon 9 intron 9 junction. None of th ese variations would be expected to affect the structure of the GCK en zyme. While none of these variants were significantly associated with IGT or NIDDM, a nonsignificant increase in the beta-cell promoter vari ant was observed in subjects with abnormal glucose tolerance. No unifo rm sequence differences in the GCK gene were identified between Japane se-American and Caucasian-American subjects. CONCLUSIONS - Mutations a ffecting the amino acid sequence of GCK do not account for the increas ed incidence of impaired glucose metabolism in Japanese-Americans, and the gene sequence does not uniformly differ from that in Caucasians.