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(Chest. 1999;115:324-328.)
© 1999 American College of Chest Physicians

Effects of Genetic Polymorphism on Ex Vivo and In Vivo Function of ß2-Adrenoceptors in Asthmatic Patients*

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

* 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.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Genetic polymorphism determines agonist-induced down-regulation and desensitization of ß2-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 of ß2-adrenoceptors in asthmatic patients, having been washed out of previous ß2-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-acting ß2-agonists for >= 48 h and short-acting ß2-agonists for >= 12 h, measurements of lymphocyte ß2-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 lymphocyte ß2-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 ß2-adrenoceptors and similarly did not influence the degree of functional antagonism exhibited by formoterol. Thus, a single dose of ß2-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic polymorphism.

Key Words: adenylyl cyclase • ß2-adrenoceptor • down-regulation • formoterol • methacholine • polymorphism


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ß 2-Adrenoceptor agonists are recommended as first-line bronchodilator therapy for relief of bronchoconstriction in patients with asthma.1 Regular treatment with long-acting ß2-agonists may be used in combination with inhaled corticosteroids and have been shown to produce additional improvements in long-term asthma control.2 Continuous exposure to regular ß2-agonist therapy may result in ß2-adrenoceptor down-regulation, which is associated with desensitization of bronchodilator and bronchoprotective activity.3

In vitro studies have shown that common variants (polymorphisms) of the ß2-adrenoceptor involving amino-acid substitutions at positions (codons) 16 and 27 of the receptor sequence result in conformational changes that determine down-regulation and desensitization in response to agonist stimulation.4 ,5 At codon 16, the glycine (Gly) polymorphism confers increased susceptibility to agonist-induced down-regulation compared with the arginine (Arg) polymorphism, whereas at codon 27, the glutamic acid (Glu) polymorphism confers resistance to down-regulation compared with the glutamine (Gln) polymorphism. In healthy volunteers with the homozygous Gly-16 genotype, repeated exposure to high-dose inhaled metaproterenol produced down-regulation and functional desensitization of lung cell ß2-adrenoceptors.6 In asthmatic patients receiving regular inhaled formoterol, the homozygous Gly-16 polymorphism was significantly more prone to bronchodilator desensitization than the Arg-16 polymorphism, with the influence of Gly-16 dominating over any putative protective effects of the Glu-27 polymorphism.7 There is also a greater propensity for a down-regulation of lymphocyte ß2-adrenoceptors in asthmatic patients with the homozygous Gly-16 polymorphism after regular treatment with inhaled formoterol.8 The Gly-16 polymorphism has also been shown to be associated with a reduced bronchodilator response to albuterol in children.9

There is also some evidence to suggest that ß2-adrenoceptor polymorphisms may be disease modifying in asthmatic patients, although they do not seem to determine the development of the asthmatic phenotype.10 For example, at codon 27, the Gln polymorphism is associated with elevated levels of IgE while the Glu polymorphism is associated with lower airway hyperreactivity to methacholine.10 ,11 At codon 16, the Gly polymorphism correlates with nocturnal asthma as well as increased airway hyperreactivity to histamine.12 ,13

To our knowledge, however, there are no published data to date on whether ß2-adrenoceptor polymorphisms at codon 16 or 27 influence basal expression or stimulated coupling of ß2-adrenoceptors in asthmatics not taking regular ß2-agonists, as opposed to agonist-promoted down-regulation and desensitization. Although the Gly-16 polymorphism appears to impart reduced bronchodilator responsiveness to albuterol, it is not known whether the same applies in terms of functional antagonism of bronchoconstriction conferred by a single dose of ß2-agonist.

The purpose of this study, therefore, was to evaluate the effects of ß2-adrenoceptor polymorphism on ex vivo lymphocyte isoproterenol stimulated adenylyl cyclase activity, as well as evaluating in vivo bronchoprotection afforded by a single dose of formoterol in asthmatic patients who have been washed out of previous ß2-agonist exposure.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Sixty patients with stable mild-to-moderate asthma were enrolled in the study; we had no prior knowledge of their ß2-adrenoceptor genotype. Analysis of ß2-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 predicted normal and to be aged between 18 and 45 years. Inhaled corticosteroids were being taken in all but three patients. All patients were using short-acting ß2-agonists on an occasional basis in a dose of < 4 puffs per day. Long-acting ß2-agonists were being taken in 9 patients and theophylline in 10 patients. All patients gave written informed consent for the study, which was approved by the Tayside Committee for Medical Research Ethics.

Protocol
Patients were requested to withhold their therapy with long-acting ß2-agonists for at least 48 h, short-acting ß2-agonists for at least 12 h, and theophylline for at least 48 h, prior to attending the laboratory between 8 and 10 AM. After a period of at least 30 min of supine rest, a venous blood sample was withdrawn for lymphocyte ß2-adrenoceptor measurements. In 48 of these patients who were found to be methacholine responsive (provocative dose causing a 20% fall in FEV1 [PD20] < 1,000 µg), an evaluation was made on the next day of the acute protective effect of formoterol dry powder, 24 µg (Oxis Turbohaler, 12 µg per actuation; Astra Pharmaceuticals; Kings Langley, UK) at 1 h after inhalation.

Measurements
Spirometry was performed according to American Thoracic Society criteria15 using a compact spirometer (Vitalograph Limited; Buckingham, UK) with a pneumotachograph head and pressure transducer and on-line computer-assisted determination of FEV1. The subjects performed three forced expiratory maneuvers and the best test value was used in the analysis. The spirometer was calibrated daily with a 1-L precision syringe, and a coefficient variation of < 3% was considered acceptable. The methacholine bronchial challenge test was performed using a previously validated standardized method.16 Methacholine was administered in doubling cumulative doses (3.125 to 6,400 µg) using a microprocessor-controlled dosimeter, given at 5-min intervals, until a 20% fall in FEV1 was recorded. The PD20 was determined by computer-assisted interpolation of the dose-response curve.

Lymphocyte ß2-adrenoceptor parameters were measured as previously described.17 In brief, receptor binding density (Bmax) and receptor binding affinity (Kd), were evaluated by ligand binding with (-)125I-iodocyanopindolol. The basal level of cyclic adenosine monophosphate (cAMP) and the maximal cAMP response (Emax) to stimulation with isoproterenol 10-4 M were measured using a radioimmunoassay technique (Incstar Ltd; Wokinham, UK). The intra-assay and interassay coefficients of variation for analytical imprecision were 5.4% and 7.2%, respectively.

ß2-Adrenoceptor polymorphisms were identified as previously described.10 In brief, genomic DNA was extracted from whole blood and a 234 base-pair fragment was generated by polymerase chain reaction that spanned the regions of interest. The genotype was determined by allele-specific oligonucleotide hybridization with probes homologous for the Arg-16, Gly-16, Gln-27, and Glu-27 forms of the ß2-adrenoceptor.

Statistical Analysis
All of the data analysis was performed using a software package (Statgraphics; STSC Software Publishing Group; Rockville, MD). The data for methacholine PD20 were logarithmically transformed to normalize their distribution. Comparisons between polymorphisms at codon 16 or codon 27 were made by an overall analysis of variance, followed by Bonferroni multiple-range testing set at 95% confidence limits. The study was powered to detect a one doubling dose difference in PD20 and a 25% difference in Emax, with the {alpha} error set a 0.05 (two-tailed). The doubling dose shift for methacholine protection afforded by formoterol was calculated using the following formula: log PD20 formoterol minus log PD20 baseline divided by log 2.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
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 ß2-agonists.


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  		Table 1. Demographic Data*

 
The results for lymphocyte ß2-adrenoceptor parameters are summarized in Table 2 . Receptor binding parameters (Bmax and Kd) showed no differences between the polymorphisms at codon 16 or 27. Basal cAMP was significantly (p < 0.05) different between Glu-27 and Het-27, but showed no differences at codon 16. Stimulated adenylyl cyclase activity (Emax) was not significantly altered by any of the polymorphisms. This was the case whether the cAMP response to isoproterenol stimulation was expressed either in absolute terms (post-Emax) or as the difference between prestimulation and poststimulation ({delta}-Emax).


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  		Table 2. Lymphocyte ß2-Adrenoceptor Parameters*

 
The baseline unprotected methacholine PD20 showed a lower geometric mean value in patients with the homozygous Gly-16 polymorphism, although this did not represent a significant difference compared with patients who were homozygous Arg-16 or who were heterozygous (Table 3 ). After inhalation of a single 24-µg dose of formoterol, there was a protective effect of between four to five doubling doses of methacholine. There was no significant difference between polymorphisms in the degree of protection afforded by formoterol.


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  		Table 3. Methacholine Bronchial Challenge*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results show that genetic polymorphism at codon 16 or 27 does not influence lymphocyte ß2-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 codon 27 or codon 16. It is unlikely that these differences in basal cAMP are important given the lack of effect of polymorphism on isoproterenol cAMP response between Glu-27 and Het-27.

The absence of polymorphism effect on stimulated adenylyl cyclase activity in lymphocytes was mirrored by the in vivo response to a single 24-µg dose of formoterol, in terms of the functional antagonism against methacholine-induced bronchoconstriction. Our results were found in patients who had been washed out of their previous long- or short-acting ß2-agonists. Thus, in our study, we were not evaluating the effects of regular ß2-agonist exposure in terms of promoting down-regulation or desensitization, as has been demonstrated in previous in vitro and in vivo studies.4 ,5 ,6 ,7 ,8 Our results showed that a single 24-µg dose of formoterol produced a shift in the methacholine dose-response curve amounting to five doubling doses, whereas regular treatment with 24 µg twice daily results in a shift of less than one doubling dose.18 We elected to use a 48-h washout period for long-acting ß2-agonists, in view of our previous observation of persistent down-regulation of lymphocyte ß2-adrenoceptors in some patients with the homozygous Gly-16 polymorphism at 36 h after stopping regular formoterol therapy.8

The results of the present study with ex vivo lymphocyte ß2-adrenoceptors are in keeping with those of Green et al4 who showed in transfected Chinese hamster fibroblast cells that receptor binding and adenylyl cyclase activity are unaltered by ß2-adrenoceptor mutations when cells have not undergone agonist exposure previously. However, our results would appear to be contradictory to those of Martinez et al,9 who showed that patients with the homozygous Gly-16 polymorphism were significantly less likely to respond to a single 180-µg dose of inhaled albuterol, as compared to patients with the homozygous Arg-16 polymorphism. In the study of Martinez et al,9 the patients were instructed to stop their ß2-agonist therapy for only 6 h before the bronchodilator test, which may have resulted in ß2-adrenoceptor down-regulation and desensitization occurring as a consequence of carryover from previous ß2-agonist therapy. Another possible difference between our study and that of Martinez et al9 is that formoterol is a higher-efficacy agonist than albuterol, which may therefore have overcome any reduction in G-protein coupling.

We used formoterol for our in vivo response to closely mirror the agonist activity of isoproterenol, which was used for the in vitro stimulation of lymphocyte ß2-adrenoceptors. The 24-µg dose of formoterol that we used, although within the clinically recommended dose range for a single dose, is approximately equivalent to a 400-µg dose of albuterol. A single 24-µg dose of formoterol coincides with the top of the dose-response curve for methacholine bronchoprotection.18 It is possible that had we used a 6-µg dose of formoterol, it may have been possible to show differences between the polymorphisms in the degree of functional antagonism. It is also worth pointing out that we did not evaluate the effects of formoterol on the slope of the methacholine dose-response curve.

We found a nonsignificant trend toward a higher degree of baseline (unprotected) bronchial hyperreactivity to methacholine in patients who were homozygous for Gly-16 compared with Arg-16. This is in keeping with a previous study using histamine in atopic subjects.13 However, we did not observe any difference in baseline hyperreactivity between homozygous genotypes at codon 27, unlike the study of Hall et al11 in which the Glu-27 polymorphism was associated with significantly lower hyperreactivity to methacholine. It is conceivable, however, that ß2-adrenoceptor polymorphism may be a more important determinant of hyperreactivity using an indirect bronchoconstrictor stimulus, as for example, using adenosine monophosphate challenge.

We accept the possible limitations of using peripheral blood lymphocytes for evaluating ex vivo ß2-adrenoceptor function. While it is conceivable that mononuclear cells in peripheral blood will behave in a similar fashion to mononuclear cells in bronchial mucosa, there is conflicting evidence as to the validity of using ß2-adrenoceptors on lymphocytes as a surrogate for ß2-adrenoceptors on bronchial smooth muscle.19 ,20 ,21 ,22 Nevertheless, there appears to be a good correlation between agonist-induced down-regulation of lymphocyte and lung ß2-adrenoceptors.22 We evaluated the cAMP response to maximal stimulation with isoproterenol, but did not perform a full dose-response curve. It is unlikely that altered ß2-adrenoceptor coupling would manifest as rightward shift in the isoproterenol dose-response curve without also blunting the maximal response.

What is the possible clinical relevance of our results? We believe it is relevant to look at the functional antagonism of a ß2-agonist against methacholine-induced bronchoconstriction, because the smooth muscle relaxant effects of ß2-agonists are highly dependent on the prevailing degree of bronchomotor tone.23 However, it may not be possible to directly extrapolate the effects of formoterol on bronchoconstriction due to methacholine to what happens in real-life situation in acute asthma.

Our study assessed ß2-adrenoceptor-mediated responses with formoterol in vivo and with isoproterenol ex vivo in the presence of essentially naive ß2-adrenoceptors, as a consequence of the washout period. Thus, the effects of ß2-agonist stimulation are a reflection of what happens in patients using their ß2-agonist as occasional reliever therapy, rather than looking at effects on top of regular ß2-agonist exposure. In the latter situation, it is known that the homozygous Gly-16 polymorphism confers a reduced bronchodilator response to formoterol.7 Our results are therefore reassuring and suggest that for patients using a single dose of ß2-agonist for occasional rescue purposes, there is no evidence of an attenuated response in association with the homozygous Gly-16 polymorphism. We also believe our findings are relevant to current asthma management guidelines in that our patients were also taking regular treatment with inhaled corticosteroids, in addition to using reliever ß2-agonists on an as-required basis.


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

Correspondence to: B.J. Lipworth, MD, Professor of Allergy and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; e-mail: b.j.lipworth@dundee.ac.uk

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

Received for publication June 22, 1998. Accepted for publication September 28, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. National Asthma Education and Prevention Program. Expert pannel report II: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, 1997; publication 97-4051
  2. Pauwels, R, Lofdahl, CG, Postma, D, et al (1997) Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 337,1405-1411[Abstract/Free Full Text]
  3. Lipworth, BJ (1997) Airway subsensitivity with long-acting beta 2-agonists: is there cause for concern? Drug Safety 16,295-308[ISI][Medline]
  4. Green, SA, Turki, J, Innis, M, et al (1994) Amino-terminal polymorphisms of the human beta-adrenergic receptor impart distinct agonist-promotive regulatory properties. Biochemistry 33,414-419
  5. Green, SA, Turki, J, Vegarno, P, et al (1995) Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airways smooth muscle cells. Am J Respir Cell Mol Biol 13,25-33[Abstract]
  6. Turki, J, Green, SA, Newman, KB, et al (1995) Human lung cell beta-adrenergic receptors desensitize in response to in vivo administered beta-agonist. Am J Physiol 269,709-714
  7. Tan, KS, Hall, IP, Dewar, J, et al (1997) Beta 2-adrenoceptor polymorphism is associated with susceptibility to bronchodilator desensitization in moderately severe stable asthmatics. Lancet 350,995-999[CrossRef][ISI][Medline]
  8. Aziz, I, Hall, IP, McFalane, LC, et al (1998) Beta 2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 101,337-341[CrossRef][ISI][Medline]
  9. Martinez, FD, Graves, PE, Baldini, M, et al (1997) Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 100,3184-3188[ISI][Medline]
  10. Dewar, J, Wilkinson, J, Wheatley, A, et al (1997) The glutamine 27 beta 2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol 100,261-265[CrossRef][ISI][Medline]
  11. Hall, IP, Wheatley, A, Wilding, P, et al (1995) Association of the Glu-27 beta 2 adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 345,1213-1214[CrossRef][ISI][Medline]
  12. Turki, J, Pak, J, Green, S, et al (1995) Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal asthma and non-nocturnal asthma: evidence that Gly-16 correlates with the nocturnal phenotype. J Clin Invest 95,1635-1641
  13. Holroyd, KJ, Levitt, RC, Dragwa, C, et al (1995) Evidence for beta 2-adrenergic receptor polymorphism at amino acid 16 as a risk factor for bronchial hyperresponsiveness. Am J Respir Crit Care Med 151(suppl),A673
  14. . American Thoracic Society. (1997) Standards for diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 136,225-244
  15. . American Thoracic Society. (1987) Standardization of spirometry—update. Am Rev Respir Dis 136,1285-1298[ISI][Medline]
  16. Beach, JR, Jung, CL, Avery, HA, et al (1993) Measurement of airway responsiveness to methacholine: relative importance of the precision of drug delivery and the method of assessing response. Thorax 418,239-243
  17. Newnham, DM, Coutie, WJ, McFarlane, LC, et al (1993) Comparison of in vitro parameters of lymphocyte beta 2-adrenoceptor function in normal and asthmatic subjects. Eur J Clin Pharmacol 45,535-538[CrossRef][ISI][Medline]
  18. Lipworth, B, Tan, S, Devlin, M, et al (1998) Effects of treatment with formoterol on bronchoprotection against methacholine. Am J Med 104,431-438[CrossRef][ISI][Medline]
  19. Davis, C, Conolly, ME, Greenacre, JK (1980) ß2-Adrenoceptors in human lung, bronchus and lymphocytes. Br J Clin Pharmacol 10,425-432[Medline]
  20. Liggett, SB, Marker, JC, Shah, SD, et al (1988) Direct relationship between mononuclear leukocyte and lung ß2-adrenergic receptors and apparent reciprocal regulation of extravascular but not intravascular alpha and beta-adrenergic receptors via the sympathochromaffin system in humans. J Clin Invest 82,48-56
  21. Hauck, RW, Bohm, M, Gengenbach, S, et al (1990) ß2-Adrenoceptors in human lung and peripheral mononuclear leukocytes of untreated and terbutaline treated patients. Chest 98,376-381[Abstract/Free Full Text]
  22. Hayes, J, Quing, F, Rhodes, CG, et al (1996) In vivo quantification of human pulmonary ß2-adrenoceptors: effects of ß-agonist therapy. Am J Respir Crit Care Med 154,1277-1283[Abstract]
  23. Molimard, M, Naline, E, Zhang, Y, et al (1998) Long- and short-acting ß2-adrenoceptor agonists: interactions in human contracted bronchi. Eur Respir J 11,583-588[Abstract]



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