Sequence analysis of the ?-ADRENERGIC receptor (ADRA2B) gene and in-vivo functional effects of novel variants

Abstract

Background ADRA2B is important in vasoconstriction and blood pressure regulation. The only common variant identified (del301–303) decreased receptor desensitization in vitro but did not alter vascular sensitivity in vivo. We therefore characterized the genetic variation in ADRA2B and related this to in vivo phenotype. Methods We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exon, and 3' flanking region) using PCR and bidirectional sequencing (n=68). Vasoconstriction in response to the selective α2AR agonist dexmedetomidine (0.01–1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. ED50 and Emax were used to compare vascular responses in subjects with and without variant alleles. Results 27 variants were detected, including the previously described 301–303 deletion, 15 in the promoter region, 5 (2 non-synonymous) in the coding region and 7 in the 3'UTR region. Among the 9 variants with a minor allele frequency >5%, 3 SNPs (T1901G and G2572T in the promoter region and G4807A in the 3'UTR) were in linkage disequilibrium and associated with a lower Emax, 61.3±23.5% (mean±SD) compared to 77.8±17.0% in wildtype subjects, P= 0.048. There was no association between the 9 common variants and ED50. Conclusion We describe novel variants of the ADRA2B gene. These do not alter sensitivity to a selective α2AR agonist but may decrease maximal venoconstriction in vivo. Clinical Pharmacology & Therapeutics (2005) 77, P25–P25; doi: 10.1016/j.clpt.2004.11.095