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dc.contributor.authorPanebra, Alfredo
dc.contributor.authorWang, Wayne C.
dc.contributor.authorMalone, Molly M.
dc.contributor.authorPitter, Demar R. G.
dc.contributor.authorWeiss, Scott Tillman
dc.contributor.authorHawkins, Gregory A.
dc.contributor.authorLiggett, Stephen B.
dc.date.accessioned2012-01-03T22:55:43Z
dc.date.issued2010
dc.identifier.citationPanebra, Alfredo, Wayne C. Wang, Molly M. Malone, Demar R. G. Pitter, Scott T. Weiss, Gregory A. Hawkins, and Stephen B. Liggett. 2010. Common ADRB2 Haplotypes Derived from 26 Polymorphic Sites Direct β2-Adrenergic Receptor Expression and Regulation Phenotypes. PLoS ONE 5(7): e11819.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:6177595
dc.description.abstractBackground: The β2-adrenergic receptor (β2AR) is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists) acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions. Methodology/Principal Findings: We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5′UTR, coding, and 3′UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that β2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. “Whole-gene” transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface β2AR protein expression compared to the others. Agonist-promoted downregulation of β2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression. Conclusions/Significance: Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of β-agonist may be influenced by certain β2AR haplotypes (expression phenotypes), while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes). An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where β2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection-based system suggest that the density of genetic information in the form of these haplotypes, or haplotype-clusters with similar phenotypes can potentially provide greater discrimination of phenotype in human disease and pharmacogenomic association studies.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0011819en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912278/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectcell signaling and trafficking structuresen_US
dc.subjectcardiovascular disordersen_US
dc.subjectheart failureen_US
dc.subjectpharmacologyen_US
dc.subjectpersonalized medicineen_US
dc.titleCommon ADRB2 Haplotypes Derived from 26 Polymorphic Sites Direct β2-Adrenergic Receptor Expression and Regulation Phenotypesen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorWeiss, Scott Tillman
dc.date.available2012-01-03T22:55:43Z
dash.affiliation.otherHMS^Medicine-Brigham and Women's Hospitalen_US
dash.affiliation.otherSPH^Molecular+Integrative Physiological Sci Progen_US
dc.identifier.doi10.1371/journal.pone.0011819*
dash.contributor.affiliatedWeiss, Scott


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