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PI‐28
Author(s) -
Kurnik D.,
Muszkat M.,
Li C.,
Sofowora G. G.,
Solus J.,
Xie H. G.,
Harris P. A.,
Jiang L.,
McMunn C.,
Ihrie P.,
Dawson E. P.,
Williams S. M.,
Wood A. J.,
Stein C. M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.049
Subject(s) - haplotype , medicine , linkage disequilibrium , allele , blood pressure , heart rate , pharmacogenetics , gene , adrenergic receptor , norepinephrine , genetics , endocrinology , biology , receptor , genotype , dopamine
BACKGROUND The α 2A ‐adrenergic receptor (ADRA2A) regulates systemic sympathetic activity and hence cardiovascular responses. The objectives of this study were to systematically search for variants in the ADRA2A gene, define its haplotype structure, and determine functional effects of genetic variants. METHODS We examined 5957 bp of contiguous sequence of ADRA2A (promoter, exonic, and 3'‐flanking region) using bi‐directional sequencing in 135 healthy subjects (85 Caucasian and 50 African‐American). Haplotypes were inferred using an expectation‐maximization algorithm. Plasma norepinephrine concentration, resting heart rate, and blood pressure were measured. RESULTS We identified 41 variants (24 novel); based on 9 selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at −1903 and C>G at −1607, identified in 3 African‐Americans) were associated with significantly increased plasma norepinephrine concentrations (376.7±6.1 vs. 218.4±95.0 pg/mL, p=0.011). There was no other significant association between genetic variants or haplotypes with phenotypes. CONCLUSION We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants do not contribute substantially to baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy subjects. Clinical Pharmacology & Therapeutics (2005) 79 , P14–P14; doi: 10.1016/j.clpt.2005.12.049