Abstract
Migration patterns in modern societies have created the opportunity to use population admixture as a strategy to identify susceptibility genes. To implement this strategy, we genotyped a highly informative ancestry marker panel of 2270 single nucleotide polymorphisms in a random population sample of African Americans (N = 1743), European Americans (N = 1000) and Mexican Americans (N = 581). We then examined the evidence for over-transmission of specific loci to cases from one of the two ancestral populations. Hypertension cases and controls were defined based on standard clinical criteria. Both case-only and case-control analyses were performed among African Americans. With the genome-wide markers we replicated the findings identified in our previous admixture mapping study on chromosomes 6 and 21 [1]. For case-control analysis we then genotyped 51 missense SNPs in 36 genes spaced across an 18.3 Mb region. Further analyses demonstrated that the missense SNP rs2272996 (or N131S) in the VNN1 gene was significantly associated with hypertension in African Americans and the association was replicated in Mexican Americans; a non-significant opposite association was observed in European Americans. This SNP also accounted for most of the evidence observed in the admixture analysis on chromosome 6. Despite these encouraging results, susceptibility loci for hypertension have been exceptionally difficult to localize and confirmation by independent studies will be necessary to establish these findings.
Highlights
Hypertension is a consequence of common lifestyle patterns in modern society and makes an important contribution to risk of cardiovascular disease
In this paper we describe the admixture linkage results for hypertension in the Dallas Heart Study, followed by an association study of all missense single nucleotide polymorphisms (SNPs) in the region identified by the admixture mapping
After examination of Hardy-Weinberg equilibrium (HWE) for possible genotyping errors and background linkage disequilibrium which may violate the assumption of the method [25], only 1,890 SNPs were used in further analyses
Summary
Hypertension is a consequence of common lifestyle patterns in modern society and makes an important contribution to risk of cardiovascular disease. The prevalence of hypertension varies among ethnic populations in the US from 25 to 40% and is an attributable cause for approximately 13% of deaths in whites and 24% in blacks [2]. Blood pressure is a moderately heritable trait and results from the combined effect of a complex set of genetic and environmental influences, with genes cumulatively accounting for 30% of the population variance [3]. Genome-wide linkage analysis has been widely applied in efforts to identify genomic regions harboring genes affecting the risk of hypertension. The observed effects are highly inconsistent, and it is well recognized that linkage analysis has limited power when applied to complex traits [5]; locus heterogeneity may further contribute to this observed inconsistency
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