Genetic variation in the human ?2B-ADRENERGIC receptor gene: Haplotypes and yohimbine response

Abstract

Background/Aims An exaggerated increase in blood presssure by α2-adrenergic receptor (α2-AR) blockade produced by infusion of the antagonist yohimbine can predict increased risk for hypertension. We assessed α2-AR's as candidate genes influencing baseline and yohimbine-promoted increase in mean arterial pressure (MAP). Methods/Results Infusion of yohimbine and genotyping of 173 healthy individuals for common polymorphisms within the three α2-AR subtypes identified a synonymous SNP in the α2B-gene (ADRA2B) as a determinant of yohimbine response. Sequencing of ADRA2B in 254 individuals identified 2 major haplotypes that differ by the presence of a 9-bp in-frame deletion (Del Glu301–303). Del/Del homozygotes were less frequent in older subjects (13.6% and 2.3% in individuals <age 40 and≥ age 40), had lower MAP at baseline and with yohimbine infusion, but had similar responses to yohimbine. Conclusion The observed decrease in frequency of Del/Del homozygotes in individuals≥ age 40 suggests that this genotype increases risk of cardiovascular mortality or morbidity, a hypothesis consistent with recent data associating the Del/Del genotype with acute coronary syndrome and sudden cardiac death. Clinical Pharmacology & Therapeutics (2005) 77, P7–P7; doi: 10.1016/j.clpt.2004.11.028