Genetic variation at the human alpha2B-adrenergic receptor locus: role in blood pressure variation and yohimbine response.

Exaggerated response to alpha2-adrenergic receptor (alpha2-AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 alpha2-AR loci (alpha2A, alpha2B, alpha2C) as candidate genes for their influence on baseline and yohimbine-mediated increase in mean arterial pressure. Because initial results with 173 individuals implicated a possible association of yohimbine response with genetic variation at a site in the alpha2B-AR gene, but not at sites in the other 2 alpha2-AR, we sequenced the alpha2B-AR gene (4.4 kb, including 1.2 kb upstream and 1.9 kb distal to the coding sequence) in those subjects and an additional 81 individuals to search for other alpha2B-AR variants. We identified 25 polymorphisms, of which 14 are previously unreported, and 2 major haplotypes that differ by the presence/absence of a 9-bp in-frame deletion that encodes Glu301 to Glu303. Frequency differences in haplotypes were observed between blacks and whites but did not predict response to yohimbine. Genotyping of 2 additional white cohorts, including 1269 individuals with extremes in blood pressure selected from >50,000 subjects, also failed to reveal an association of the 2 major alpha2B-AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in alpha2-AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension.