The subunits of the heterotrimeric G proteins are attractive candidate gene products for both susceptibility to essential hypertension and interindividual variation in blood pressure. There is alternative splicing of exon 9 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3) associated with a C-->T change at nucleotide 825, which activates a cryptic splice site. The 825T allele results in a gene product that is 41 amino acids smaller than the wild-type gene product. G protein heterotrimers containing the shorter variant are more reactive than those containing the wild type, and the 825T allele appears to be associated with essential hypertension. To evaluate whether this variant is associated with hypertension or blood pressure in other human samples, we genotyped 447 young adult Oji-Cree for the GNB3 C825T variation. We found that the frequency of the GNB3 825T allele was 0.501 in the Oji-Cree, which is considerably higher than the frequency observed in whites. Furthermore, genetic variation of the GNB3 nucleotide 825 was significantly associated with variation in systolic pressure but not diastolic pressure. Specifically, subjects with the 825T/T genotype had significantly lower systolic pressure than subjects with the 825C/T and 825C/C genotypes; the association was independent of sex. Furthermore, the 825T allele frequency tended to be higher in subjects who took antihypertensive medications than in subjects who did not (0.571 versus 0.496; P=NS), although this young sample had relatively few subjects with hypertension. The findings support an association of variation in this gene with variation in blood pressure.