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.
Etzel
Jason P
JP
Department of Medicine, University of California at San Diego, CA, USA.
Rana
Brinda K
BK
Wen
Gen
G
Parmer
Robert J
RJ
Schork
Nicholas J
NJ
O'Connor
Daniel T
DT
Insel
Paul A
PA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D044383:Black People / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects*; D002874:Chromosome Mapping; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D014644:Genetic Variation; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D011110:Polymorphism, Genetic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D044465:White People / Q000235:genetics; D015016:Yohimbine / Q000494:pharmacology*
C547771:ADRA2B protein, human; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine