Associations between polymorphisms of the G-protein coupled receptors and intermediate phenotypes in hypertensive families

Background. Studies have demonstrated that variants of the polymorphisms of the G protein-coupled receptors are associated with hypertension and decreased vasodilation. No study, however, has investigated associations between all common polymorphisms of the candidate genes encoding these receptors and intermediate phenotypes of hypertension, controlling for population stratification in a family-based population.; Methods and results. A total of 608 subjects from 141 African-American and Caucasian families were selected on the basis of a hypertensive proband. An extensive re-sequencing of the candidate genes α _1B adrenergic receptor, β₂ adrenergic receptor, and dopamine receptor D1 on chromosome 5q in 92 subjects identified all common single nucleotide polymorphisms that were subsequently genotyped in the entire population. Associations between polymorphisms and phenotypes were tested with the Quantitative Transmission Disequilibrium Test, a test that can model both allelic transmission and linkage. Intermediate phenotypes examined in this study included baroreceptor and α₁ pressor sensitivity, autonomic responses to changes in blood pressure upon infusion of pharmacologic agents. Highly significant associations were found between α₁ pressor sensitivity and 4 promoter polymorphisms (C-468G, T-367C, T-47C, T-20C (range of p-values: .0008–.017)), and 1 coding polymorphism (C79G, p-value = .005) in the β₂ adrenergic receptor gene. Permutation tests confirmed these results, thus reducing the chance of type I errors potentially arising from violations of multivariate normality or multiple testing. Haplotypes were constructed from the polymorphisms in the β₂ adrenergic receptor gene and analyzed for associations. A comparison of models developed from haplotypes and single nucleotide polymorphisms revealed similarities with the one notable exception Arg16Gly (p = .005). Consistent with our earlier findings, this highly publicized polymorphism was not associated with any of our traits.; Conclusion. Allelic variants of the β₂ adrenergic receptor locus are associated with early functional alterations in baroreceptor sensitivity and α₁ pressor responsiveness, and may thus play an important role in the pathogenesis of essential hypertension. Taken together with recent in vitro functional testing, the findings highlight the need for examining not just one, but multiple polymorphisms and their haplotypes in allelic association analyses.