Abstract
BackgroundIn vitro and some in vivo studies suggested that genetic haplotypes may have an impact on β2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs) in the β2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of β2-adrenoceptor haplotypes on β2-agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics.MethodsPatients were genotyped for the part of the β2-adrenoceptor gene with a known bearing on receptor function and regulation. Cumulative dose response curves of fenoterol versus PD20 methacholine and FEV1 were constructed after 2 week treatment periods with either terbutaline or placebo in a double blind, randomised and cross-over design. Analysis of the dose response curves was based on a repeated measurement analysis of covariance.ResultsIn our study population comprising 45 asthmatic patients, we found three limited allelic haplotypes, resulting in six different genotypes. Our data support the existence of differences between these six genotypes both in the shape of the dose response relationship of the β2-adrenoceptor agonist fenoterol as well as in the propensity to develop tolerance for these effects by pre-treatment with terbutaline. However, this could only be substantiated for the endpoint PD20 methacholine.ConclusionBetween β2-adrenoceptor genotypes differences exist both in baseline β2-agonist induced airway responses as well as in the propensity to develop tolerance during maintenance β2-agonist therapy. The net differences after two weeks of therapy are, however, of magnitudes that are unlikely to be of clinical significance.
Highlights
In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on β2-agonist mediated airway responses in asthmatics
In an ex vivo study using human peripheral blood lymphocytes no impact of either polymorphism could be substantiated on baseline receptor expression or responsiveness[8]
Linkage disequilibrium was found between nucleotides -367 T/C, -47 T/C (coding for Arg/Cys19 of the 5' leader peptide (5'LP)), -20 T/C and + 46 A/G
Summary
In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on β2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs) in the β2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of β2-adrenoceptor haplotypes on β2agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics. Over the past decade an increasing number of single nucleotide polymorphisms (SNPs) in the β2-adrenoceptor (β2-AR) gene have been identified. In vitro these amino acid changes appeared to alter the susceptibility to receptor downregulation by exposure to β2-agonists [1,2] These observations fuelled a number of clinical and in vitro/ex vivo studies yielding inconsistent and sometimes conflicting results. In an ex vivo study using human peripheral blood lymphocytes no impact of either polymorphism could be substantiated on baseline receptor expression or responsiveness[8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
