-6A PROMOTER VARIANT OF ANGIOTENSINOGEN AND BLOOD-PRESSURE VARIATION IN CANADIAN OJI-CREE

We previously reported significant associations between variation in t he AGT gene at codon 235 and both systolic pressure and hypertension i n Canadian Oji-Cree. Recently, Inoue et al suggested that the AGT T235 variant was not causative, but was rather in linkage disequilibrium w ith a variant in the AGT promoter, namely -6A, that was associated wit h increased in vitro expression of angiotensinogen and was thus a stro ng candidate to be the functional basis of the previously observed ass ociations. We genotyped 518 adult Oji-Cree for the AGT promoter polymo rphism and tested for its association with blood pressure and hyperten sion. We found that the frequency of the -6A variant was 0.85 in the O ji-Cree, which is much higher than the frequency observed in other hum an samples. We also found strong linkage disequilibrium between the AG T -6A and T235 variants. However, genetic variation of the AGT promote r was only marginally associated with variation in systolic pressure, with a trend to significantly higher systolic pressure seen in AGT -6A /A homozygotes than in subjects with other genotypes. In addition, gen etic variation of the AGT promoter tended to be associated with a diag nosis of hypertension. Despite the very high prevalence of -6A, our na tive sample was essentially normotensive. Our findings are consistent with a marginally deleterious effect of the AGT -6A allele on blood pr essure, but linkage disequilibrium with another causative variant cann ot be ruled out in this sample of aboriginal Canadians.