title: Limited impact of multiple 5' single-nucleotide polymorphisms on the transcriptional control of the human beta 2-adrenoceptor gene.
abstract: The human beta(2)-adrenoceptor (beta(2)-AR) is subject to agonist-induced down-regulation. The degree of down-regulation is associated with certain single-nucleotide polymorphisms (SNPs) through yet unknown mechanisms. The 5'-leader sequence of the beta(2)-AR gene contains several SNPs that are in strong linkage disequilibrium. The -367 T/C polymorphism, in particular, has been shown to affect transcriptional activity in reporter gene assays. In the present study we analysed the impact of this -367 SNP on the transcription rate of the beta(2)-AR gene in the context of the complete natural locus. Taking advantage of the additional full disequilibrium with the +79 SNP in the beta(2)-AR coding sequence, allele-specific transcript quantification was performed in PBMCs of six -367 heterozygous mild asthmatic patients. Our data are in line with the reported impact of the -367 SNP and give no indication of additional haplotype-related effects on beta(2)-AR transcription. We further show that the -367 SNP affects the binding of a yet unidentified transcription factor complex, whose binding activity is not modulated by pharmacological compounds that induce or down-regulate beta(2)-AR expression, suggesting a role in constitutive steady state expression rather than in inducible expression. As the beta(2)-AR allele with a higher transcription rate associates with stronger agonist-induced down-regulation, it is not likely that the -367 SNP is causally related to the degree of down-regulation.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Westland
authors.forename: Anneke
authors.initials: A
authors.lastname: van Veen
authors.forename: Henk M
authors.initials: HM
authors.lastname: Jansen
authors.forename: Rene E
authors.initials: RE
authors.lastname: Jonkers
authors.forename: Eddy A
authors.initials: EA
authors.lastname: Wierenga
mesh_terms: D020121:5' Untranslated Regions; D001249:Asthma / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018343:Receptors, Adrenergic, beta-2