Limited beta2-adrenoceptor haplotypes display different agonist mediated airway responses in asthmatics.
BACKGROUND
In vitro and some in vivo studies suggested that genetic haplotypes may have an impact on beta2-agonist mediated airway responses in asthmatics. Due to strong linkage disequilibrium the single nucleotide polymorphisms (SNPs) in the beta2-adrenoceptor gene result in only a limited number of haplotypes. We intended to evaluate the impact of beta2-adrenoceptor haplotypes on beta2-agonist mediated airway responses and the development of tolerance in mild to moderate asthmatics.


METHODS
Patients were genotyped for the part of the beta2-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.


RESULTS
In 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 beta2-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.


CONCLUSIONS
Between beta2-adrenoceptor genotypes differences exist both in baseline beta2-agonist induced airway responses as well as in the propensity to develop tolerance during maintenance beta2-agonist therapy. The net differences after two weeks of therapy are, however, of magnitudes that are unlikely to be of clinical significance.
van Veen
Anneke
A
Department of Pulmonology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. a.vanveen@amc.uva.nl
Wierenga
Eddy A
EA
Westland
Robert
R
Weller
Frank R
FR
Hart
Guus A M
GA
Jansen
Henk M
HM
Jonkers
René E
RE
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005280:Fenoterol / Q000008:administration & dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D015990:Placebo Effect; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D016210:Methacholine Chloride; D005280:Fenoterol