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OBJECTIVE--The association between the E23K polymorphism of ATP-sensitive K[sup +] channel subunit Kir6.2 and diabetes has been reported in Caucasians but not in Asians. We examined this issue in follow-up and cross-sectional studies in a general Japanese population. RESEARCH DESIGN AND METHODS--In a 14-year follow-up study of 976 subjects aged 40-79 years with normal glucose tolerance (NGT), we investigated the impact of the E23K polymorphism on change of glucose tolerance status using a 75-g oral glucose tolerance test. Additionally, we confirmed this association in a cross-sectional survey of 2,862 subjects. RESULTS--In the follow-up study, the frequencies of the K/K genotype or K-allele were significantly higher in subjects with conversion from NGT to diabetes than in those in whom NGT was maintained (genotypes, P = 0.01; alleles, P = 0.008). In multivariate analysis, the risk for progression to diabetes was significantly higher in subjects with the E/K (odds ratio 2.10 [95% CI 1.16-3.83]) and K/K (2.40 [1.01-5.70], P for trend = 0.01) genotypes than in those with the E/E genotype after adjustment for confounding factors, namely, age, sex, fasting plasma glucose, family history of diabetes, BMI, physical activity, current drinking, and current smoking. In the cross-sectional study, the frequencies of the K/K genotype or K-allele were also significantly higher in those with diabetes than in those with NGT (genotypes, P = 0.006; alleles, P = 0.001). CONCLUSIONS--Our findings suggest that the Kir6.2 E23K polymorphism is an independent genetic risk factor for diabetes in the general Japanese population. Diabetes 56:2829-2833, 2007 [ABSTRACT FROM AUTHOR]