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(Hypertension. 2005;45:1207.)
© 2005 American Heart Association, Inc.

Original Articles

Genetic Variation at the Human _2B-Adrenergic Receptor Locus

Role in Blood Pressure Variation and Yohimbine Response

Jason P. Etzel; Brinda K. Rana; Gen Wen; Robert J. Parmer; Nicholas J. Schork; Daniel T. O’Connor; Paul A. Insel

From the Departments of Medicine (G.W., R.J.P., D.T.O., P.A.I.), Pharmacology (J.P.E., P.A.I.), and Psychiatry (B.K.R., N.J.S.), and Polymorphism Research Laboratory (B.K.R., N.J.S.), University of California at San Diego; and the VA San Diego Healthcare System (D.T.O.), San Diego, Calif.

Correspondence to Paul A. Insel, MD or Daniel T. O’Connor, MD, Department of Pharmacology, 0636 9500 Gilman Drive, BSB 3076, La Jolla, CA 92093-0636. E-mail pinsel{at}ucsd.edu; doconnor@ucsd.edu

Exaggerated response to ₂-adrenergic receptor (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 ₂-AR loci (_{2A, 2B, 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 _2B-AR gene, but not at sites in the other 2 ₂-AR, we sequenced the _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 _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 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 _2B-AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in ₂-AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension.

Key Words: receptors, adrenergic alpha • haplotypes • SNP • intermediate phenotype

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