Genetic Variation at the Human  2B-Adrenergic Receptor Locus: Role in Blood Pressure Variation and Yohimbine Response

Exaggerated response to alpha(2)-adrenergic receptor (alpha(2)-AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 alpha(2)-AR loci (alpha(2A), alpha(2B), alpha(2C)) 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 alpha(2B)-AR gene, but not at sites in the other 2 alpha(2)-AR, we sequenced the alpha(2B)-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 alpha(2B)-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 Glu(301) to Glu(303). 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 alpha(2B)-AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in alpha(2)-AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension.