0
Clinical Investigations: ASTHMA |

Effects of Genetic Polymorphism on Ex Vivo and In Vivo Function of β2-Adrenoceptors in Asthmatic Patients*

Brian J. Lipworth, MD; Ian P. Hall, MD; Soong Tan, MBChB; Imran Aziz, MBChB; Wendy Coutie, HNC
Author and Funding Information

*From the Department of Clinical Pharmacology and Therapeutics and Department of Respiratory Medicine, (Drs. Lipworth, Tan, and Aziz, and Ms. Coutie), Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK; and the Department of Therapeutics (Dr. Hall), University Hospital, Nottingham, UK.



Chest. 1999;115(2):324-328. doi:10.1378/chest.115.2.324
Text Size: A A A
Published online

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.

Abbreviations: Arg = homozygous arginine; Bmax = receptor binding density; cAMP = cyclic adenosine monophosphate; Emax = maximal cyclic adenosine monophosphate response; Glu = homozygous glutamic acid; Gly = homozygous glycine; Het = heterozygous; Kd = receptor binding affinity; PD20 = provocative dose causing a 20% fall in FEV1


Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Figures

Tables

References

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Sign In to Access Full Content

MEMBER & INDIVIDUAL SUBSCRIBER

Want Access?

NEW TO CHEST?

Become a CHEST member and receive a FREE subscription as a benefit of membership.

Individuals can purchase this article on ScienceDirect.

Individuals can purchase a subscription to the journal.

Individuals can purchase a subscription to the journal or buy individual articles.

Learn more about membership or Purchase a Full Subscription.

INSTITUTIONAL ACCESS

Institutional access is now available through ScienceDirect and can be purchased at myelsevier.com.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543