Variations in the α2A-adrenergic receptor gene and their functional effects

Daniel Kurnik, Mordechai Muszkat, Chun Li, Gbenga G. Sofowora, Joseph Solus, Hong Guang Xie, Paul A. Harris, Lan Jiang, Chara McMunn, Patrick Ihrie, Elliott P. Dawson, Scott M. Williams, Alastair J.J. Wood*, C. Michael Stein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Background and Objectives: The α2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. Methods: We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3′-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. Results: We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 ± 6.1 pg/mL versus 218.4 ± 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. Conclusion: We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers.

Original languageAmerican English
Pages (from-to)173-185
Number of pages13
JournalClinical Pharmacology and Therapeutics
Volume79
Issue number3
DOIs
StatePublished - Mar 2006

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