A −30G>A Polymorphism of the β-Cell–Specific Glucokinase Promoter Associates With Hyperglycemia in the General Population of Whites

Abstract

A graded relationship has been reported between fasting and postprandial plasma glucose levels and the subsequent risk of cardiovascular morbidity and mortality. We hypothesized that the GCK −30G>A promoter polymorphism is associated with elevated glycemia in the middle-aged general population of whites, as well as with features of the World Health Organization (WHO)-defined metabolic syndrome. The GCK −30G>A polymorphism was genotyped in the population-based Inter99 study cohort (5,965 subjects) and in 332 nondiabetic subjects and 1,063 patients with type 2 diabetes. In the Inter99 cohort, the GCK −30A allele was associated with increased fasting (P < 0.001) and post–oral glucose tolerance test (OGTT) plasma glucose levels (P < 0.001), and in the same cohort, the GCK −30A allele was more frequent among 1,325 subjects with the metabolic syndrome than among 1,679 subjects without any components of the metabolic syndrome (P = 0.002). Moreover, the GCK −30A allele frequency was higher among 2,587 subjects with impaired glucose regulation (IGR) than among 4,773 glucose-tolerant subjects (17.3% [95% CI 16.2–18.3] vs. 15.0% [14.3–15.7], P < 0.001, odds ratio GG vs. GA 1.21 [1.08–1.36], GG vs. AA 1.62 [1.17–2.24]). In conclusion, the GCK −30G>A polymorphism associates with elevated fasting and post-OGTT glycemia in the middle-aged general population of whites, as well as with IGR and other features of the WHO-defined metabolic syndrome.