POLYMORPHIC MICROSATELLITE REPEAT MARKERS AT THE GLUCOKINASE GENE LOCUS ARE POSITIVELY ASSOCIATED WITH NIDDM IN JAPANESE

To assess the possible role of glucokinase defects contributing to a g enetic susceptibility to NIDDM in Japanese, allelic frequencies of two microsatellite repeat polymorphisms, one in the 3'-flanking region (G CK1) and the other in the 5'-flanking region (GCK2) of the human gluco kinase gene, were analyzed in subjects with NIDDM and in nondiabetic c ontrol subjects. After typing 107 diabetic and 74 nondiabetic subjects , we found four GCK1 alleles (Z, Z2, Z4, Z6) and six GCK2 alleles (0, -4, -2, 2, 4, 8). The frequency distribution of GCK1 alleles was diffe rent between the two groups (P = 0.005), although not significant afte r correction for multiple comparisons. The Z4 allele was found more fr equently in diabetic than in nondiabetic subjects (23 vs. 10%, P = 0.0 02). This was still significant after correction for multiple comparis ons (P < 0.05). The frequency distribution of GCK2 alleles was not dif ferent between the two groups. However, the -2 allele was more common in diabetic than in nondiabetic subjects (P = 0.044), although not sig nificant after adjusting for multiple comparisons. Clinical characteri stics were compared between the diabetic subjects with Z4 and/or -2 al lele and those without either of these two alleles. No differences wer e found in the age of diagnosis, positive family history, mode of ther apy, current HbA1c, or dally urinary C-peptide immunoreactivity excret ion between the two groups. We demonstrated a significant association between GCK1 and GCK2 alleles and NIDDM. The results indicate that the polymorphic alleles GCK1 and GCK2 could be genetic markers in NIDDM i n Japanese, suggesting a relationship between glucokinase defects and the susceptibility to NIDDM in this population.