Previous studies have shown that the T allele of the GNAS1 T393C polymorphism is associated with poor responsiveness to β-blockade and that the T393C polymorphism interacts with cigarette smoking and alcohol consumption in the pathogenesis of hypertension. Thus, the T393C polymorphism is likely to interact with β-adrenoceptor (β-AR) stimulation in the pathogenesis of hypertension. Although this interaction might be caused by a direct effect of Gs proteins on the cardiovascular system, it could also result from an indirect effect of Gs proteins mediated by glucose metabolism. Moreover, association studies are often irreproducible. We therefore examined the possible interaction between the T393C polymorphism and γ-glutamyl transpeptidase (GGT), which is an established biomarker of alcohol consumption, in the association with glucose metabolism as well as with hypertension in a Japanese population. Genotyping for GNAS1 was performed by using the polymerase chain reaction-restriction fragment length polymorphism method in all 821 samples. The present study showed a significant interaction between the T393C polymorphism and GGT in the association with hypertension (p =0.033). This interaction was even more significant after adjustment for all confounding factors (p =0.0025). In contrast, analysis of the possible interaction of the T393C polymorphism with GGT in the association with diabetes mellitus or fasting plasma glucose failed to show a significant result. These results did not support the hypothesis that the interaction between the T393C polymorphism and GGT in the association with hypertension could be caused by an indirect effect of Gs proteins mediated by glucose metabolism. (Hypertens Res 2004; 27: 919-924)