ORIGINAL ARTICLESVariation in the α2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivoMuszkat, Mordechaia; Kurnik, Daniela; Solus, Josephc; Sofowora, Gbenga G.a; Xie, Hong-Guanga; Jiang, Lanb; McMunn, Charac; Ihrie, Patrickc; Harris, James R.c; Dawson, Elliott P.c; Williams, Scott M.a b; Wood, Alastair J.J.a; Michael Stein, C.aAuthor Information aDepartments of Medicine and Pharmacology, Division of Clinical Pharmacology bCenter for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee cBioventures Inc., Murfreesboro, Tennessee, USA Sponsorship: This study was supported in part by US Public Health Service grants HL04012, GM-5MO1-00095, GM31304, and the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org under grant U01HL65962). Drs Muszkat and Kurnik are recipients of a Merck Sharp and Dohme International Fellowship in Clinical Pharmacology. Correspondence and requests for reprints to C. Michael Stein, Division of Clinical Pharmacology, 560 RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA Tel: +1 615 343 8701; fax: +1 615 343 2551; e-mail: [email protected] Received 21 February 2005 Accepted 21 March 2005 Pharmacogenetics and Genomics: June 2005 - Volume 15 - Issue 6 - p 407-414 Buy Abstract The α2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2B gene (del301–303) has been identified, and results in markedly decreased receptor desensitization in vitro but does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2B and related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exonic, and 3′-untranslated region; 3′-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n=68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective α2-adrenergic receptor agonist, dexmedetomidine (0.01–1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose–response curves. ED50 and Emax were compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3′-UTR region. Four haplotypes were inferred, representing approximately 95% of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3′-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3% [95% confidence interval (CI) 39.5–83.0, n=7] compared to 78.1% (CI 73.8–82.5) in wild-types (n=61) (P=0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2B gene. These do not alter sensitivity to a selective α2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo. © 2005 Lippincott Williams & Wilkins, Inc.