Variable-length poly-C tract polymorphisms of the beta2-adrenergic receptor 3'-UTR alter expression and agonist regulation.
Beta(2)-adrenergic receptors (beta(2)-AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for beta-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5'-flanking or coding region of the intronless beta(2)-AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3'-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the beta(2)-AR (Arg16) coding sequence followed by its 3'-UTR with the various polymorphic poly-C tracts. beta(2)Arg16-11C had 25% lower mRNA expression and 33% lower beta(2)-AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, beta(2)Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with beta(2)Arg16-12C and -13C. However, beta(2)Arg16-12C underwent 50% less downregulation of receptor expression during beta-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (beta(2)Arg16-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (beta(2)Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to beta-agonist, and genotyping to identify these 3'-UTR polymorphisms may improve predictive power within the context of beta(2)-AR haplotypes in pharmacogenetic studies.
Panebra
Alfredo
A
Cardiopulmonary Genomics Program, University of Maryland School of Medicine, 20 Penn Street, Baltimore, MD 21201-1075, USA.
Schwarb
Mary Rose
MR
Swift
Steven M
SM
Weiss
Scott T
ST
Bleecker
Eugene R
ER
Hawkins
Gregory A
GA
Liggett
Stephen B
SB
D020413:3' Untranslated Regions / Q000235:genetics*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics; D011066:Poly C / Q000235:genetics*; D011110:Polymorphism, Genetic; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D011066:Poly C