title: -6A promoter variant of angiotensinogen and blood pressure variation in Canadian Oji-Cree.
abstract: We previously reported significant associations between variation in the AGT gene at codon 235 and both systolic pressure and hypertension in Canadian Oji-Cree. Recently, Inoue et al suggested that the AGT T235 variant was not causative, but was rather in linkage disequilibrium with a variant in the AGT promoter, namely -6A, that was associated with increased in vitro expression of angiotensinogen and was thus a strong candidate to be the functional basis of the previously observed associations. We genotyped 518 adult Oji-Cree for the AGT promoter polymorphism and tested for its association with blood pressure and hypertension. We found that the frequency of the -6A variant was 0.85 in the Oji-Cree, which is much higher than the frequency observed in other human samples. We also found strong linkage disequilibrium between the AGT -6A and T235 variants. However, genetic variation of the AGT promoter 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, genetic variation of the AGT promoter tended to be associated with a diagnosis of hypertension. Despite the very high prevalence of -6A, our native sample was essentially normotensive. Our findings are consistent with a marginally deleterious effect of the AGT -6A allele on blood pressure, but linkage disequilibrium with another causative variant cannot be ruled out in this sample of aboriginal Canadians.
authors.affiliation: St. Michael's Hospital, Toronto, Ontario, Canada. robert.hegele@rri.on.ca
authors.forename: R A
authors.initials: RA
authors.lastname: Hegele
authors.forename: S B
authors.initials: SB
authors.lastname: Harris
authors.forename: A J
authors.initials: AJ
authors.lastname: Hanley
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.forename: P W
authors.initials: PW
authors.lastname: Connelly
authors.forename: B
authors.initials: B
authors.lastname: Zinman
mesh_terms: D000328:Adult; D000808:Angiotensinogen / Q000235:genetics*; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics*; D002170:Canada; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007198:Indians, North American / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D017931:DNA Primers; D000808:Angiotensinogen