The mechanism of human G beta mutation, G beta3-s, to produce a "gain-of-function" G-protein signaling abnormality remains to be elucidated. Both the enhanced Gi-mediated signalings and the expression of G beta3-s have been demonstrated to be associated with hypertension, together with the finding that the T825 variant might be associated with the occurrence of a splice variant GNB3-s in a white population. The aim of the present study was to reveal a key role of G beta by confirming the association between this polymorphism and susceptibility of hypertension in Japanese. Genotype analysis of 180 normotensive and 179 hypertensive subjects suggests that the T allele tends to be related to the prevalence of hypertension. When age, sex and body mass index were controlled by multiple logistic regression, odds ratios for hypertension associated with the T allele were 1.77 (TT vs CC; 95% confidence interval (CI) 0.97-3.21; p = 0.06), 1.13 (TC vs CC; 95% CI 0.62-2.05; p = 0.69) and 1.40 (TT + TC vs CC; 95% CI 0.81-2.40; p = 0.23). The T allele frequency was found to be significantly higher in hypertensives than in normotensives (0.63 vs 0.56; chi2 = 4.27; p = 0.04), both of which are considerably higher than the frequency observed in Whites. Higher T allele frequencies in Japanese may represent one of the ethnic differences: a larger subgroup whose hypertension is increased by excessive salt diet. Confirming the association between the T allele and hypertension by further investigation and then utilizing the various intermediate features or phenotypes, such as Na+/H+ exchanger activity and renin levels, may help to unravel the active role of the beta subunit.