EARLY-ONSET TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS IS ASSOCIATED WITH GLUCOKINASE LOCUS, BUT NOT WITH ADENOSINE-DEAMINASE LOCUS, IN THE JAPANESE POPULATION

To investigate the possible contribution of glucokinase (GCK) and adenosine deaminase (ADA) loci to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes mellitus, we studied the association of these loci with type 2 diabetes in the Japanese population. Fifty patients with type 2 diabetes and 50 control subjects were analyzed for microsatellite polymorphism 3' to the GCK gene and PstI polymorphism in the ADA gene by polymerase chain reaction. The frequency of the most common GCK allele (Z) was significantly lower in type 2 diabetic patients than that in control subjects and a longer Z + 2 allele was more common in type 2 diabetic patients (26% vs. 15%, P = 0.053), particularly in those with younger age of onset (33% vs. 15%, younger onset type 2 diabetes vs. control, P = 0.014). The frequency of genotypes containing at least one Z + 2 allele was significantly more common in type 2 diabetic patients (46% vs. 28%, P < 0.05), particularly in those with younger age of onset (61% vs. 28%, relative risk 4.00, P < 0.01). In contrast, there was no difference in allelic or genotypic frequencies of PstI polymorphism in the ADA gene between the two groups. Despite the association between the GCK locus and type 2 diabetes, none of the patients had known mutations (GlU(265) --> AM(265), GlU(279) --> AM(279), Gly(299) --> Arg(299), GlU(300) --> Gln(300), Leu(309) --> Pro(309)). These results suggest that the GCK locus, but not the ADA locus, contributes to the genetic susceptibility to type 2 diabetes in Japanese. The low frequencies of known GCK mutations shown in this and other studies suggest that the association of the GCK locus with type 2 diabetes observed in this study is due to the presence of an unknown common mutation in exons or a mutation in the regulatory region of the GCK gene.