Chest
Volume 115, Issue 2, February 1999, Pages 324-328
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Clinical Investigations
ASTHMA
Effects of Genetic Polymorphism on Ex Vivo and In Vivo Function of β2-Adrenoceptors in Asthmatic Patients

https://doi.org/10.1378/chest.115.2.324Get rights and content

Background

Genetic polymorphism determines agonist-induced down-regulation and desensitization ofβ 2-adrenoceptors.

Objectives

The aim of the present study was to investigate the effects of genetic polymorphism on ex vivo (lymphocytes) and in vivo (bronchoprotection) function ofβ 2-adrenoceptors in asthmatic patients, having been washed out of previous β2-agonist exposure.

Methods

Sixty patients with stable mild-to-moderate asthma were evaluated, with a post hoc analysis of genotype performed at end of study. Having withheld treatment with long-actingβ 2-agonists for ≥ 48 h and short-actingβ 2-agonists for ≥ 12 h, measurements of lymphocyteβ 2-adrenoceptors were made for binding density, binding affinity, basal cyclic adenosine monophosphate (cAMP), and maximal cAMP response to isoproterenol (Emax). In addition, in 48 of these patients who were methacholine responsive (PD20 < 1,000 μg), the acute protective effect of formoterol as a 24-μg single dose (at 1 h) was also evaluated. Comparisons were made according to homozygous and heterozygous (Het) polymorphisms at codon 16 and codon 27.

Results

There were no significant differences in age, FEV1 percent predicted, or inhaled corticosteroid dose, when comparing mean values for polymorphisms at either codon 16 or codon 27. There were also no significant differences between polymorphisms for any of the measured lymphocyteβ 2-adrenoceptor parameters apart from basal cAMP between Glu-27 and Het-27. Mean values for Emax (after-before isoproterenol as pmol/106 cells) were as follows: Gly-16 (3.4), Arg-16 (3.5), Het-16 (4.0), Glu-27 (3.9), Gln-27 (3.5), and Het-27 (3.7). Polymorphism had no significant effect on formoterol protection as doubling dose shift in methacholine PD20 (geometric mean): Gly-16 (5.3), Arg-16 (5.4), Het-16 (4.6), Glu-27 (5.3), Gln-27 (5.3), Het-27 (4.5).

Conclusions

Our results show that genetic polymorphism at codon 16 or 27 does not influence stimulated coupling of lymphocyte β2-adrenoceptors and similarly did not influence the degree of functional antagonism exhibited by formoterol. Thus, a single dose of β2-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic polymorphism.

Section snippets

Patients

Sixty patients with stable mild-to-moderate asthma were enrolled in the study; we had no prior knowledge of theirβ 2-adrenoceptor genotype. Analysis ofβ 2-adrenoceptor polymorphism was subsequently performed on a post hoc basis in all patients at the end of the study. All patients were required to have a diagnosis of stable asthma of mild-to-moderate severity, according to American Thoracic Society criteria.14 All patients were nonsmokers and were required to have an FEV1 of at least 60% of

Results

The demographic data are summarized in Table 1 for homozygous and heterozygous (Het) polymorphisms at codon 16 and 27. There were no significant differences between the polymorphisms for age, FEV1, or inhaled corticosteroid dose. Moreover, there were no differences between the groups in terms of prior use of long- or short-acting β2-agonists.

The results for lymphocyte β2-adrenoceptor parameters are summarized in Table 2. Receptor binding parameters (Bmax and Kd) showed no differences between

Discussion

Our results show that genetic polymorphism at codon 16 or 27 does not influence lymphocyte β2-adrenoceptor binding density or affinity. There was also no impairment of functional coupling to the G-protein as evidenced by maximal isoproterenol-stimulated adenylyl cyclase activity, which was similar for each of the polymorphisms. Although basal cAMP activity was significantly different between Glu-27 and Het-27, there was no difference when comparing the two homozygous polymorphisms at either

References (23)

  • J Turki et al.

    Human lung cell beta-adrenergic receptors desensitize in response to in vivo administered beta-agonist

    Am J Physiol

    (1995)
  • Cited by (0)

    This study was supported by a joint grant from the Universities of Dundee and Nottingham. Dr. Hall is a National Asthma Campaign supportedsenior research fellow. Dr. Tan was also supported by the National Asthma Campaign.

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