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Bronchodilator Response in Relation to 2-Adrenoceptor Haplotype in Patients with Asthma

Otago Respiratory Research Unit and Department of Preventive and Social Medicine, Dunedin School of Medicine; and Canterbury Respiratory Research Unit and Department of Pathology, Gene Structure and Function Laboratory, Christchurch School of Medicine, University of Otago, Dunedin, New Zealand

Correspondence and requests for reprints should be addressed to Professor D. Robin Taylor, M.D., F.R.C.P.(C)., Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand. E-mail: robin.taylor{at}stonebow.otago.ac.nz

	ABSTRACT

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Rationale: Genetic variation of the 2-adrenoceptor (ADRB2) influences receptor function in vitro. There are reports that, in vivo, bronchodilator response is related to ADRB2 genotype, and that clinical outcomes during chronic therapy with 2-agonist drugs are also influenced by genotype. Whether these features are related to single nucleotide polymorphisms or to combinations (haplotypes) is unclear. Objectives: Our aim was to measure bronchodilator response in patients with asthma stratified by ADRB2 haplotype. This was done after eliminating the confounding effect of prior drug treatment with inhaled 2-agonists and corticosteroids. Methods: ADRB2 haplotype was determined in 176 patients with asthma, of whom 161 harbored the six most common combinations. Treatment with inhaled 2-agonists and inhaled corticosteroids was withheld for appropriate intervals. Spirometric changes 20 minutes after a single dose of albuterol (2.5 mg by nebulizer) were then recorded. Results: There were no significant differences in bronchodilator response (% improvement in FEV₁) with respect to any of the major ADRB2 haplotypes or genotypes. Conclusions: Genetic variation of the ADRB2 does not influence the immediate response to inhaled 2-agonist. The confounding effect of tolerance resulting from regular 2-agonist use must be controlled when assessing the pharmacogenetic influences on clinical outcomes with 2-agonists.

Key Words: asthma therapy • 2-adrenoceptor • 2-agonist • haplotype

Single nucleotide polymorphisms (SNPs) of the 2-adrenoceptor (ADRB2) and its regulator peptide are common (1), and in vitro studies have demonstrated their functional importance (2–6). Amino-acid substitutions at positions 16 (Gly to Arg) and 27 (Gln to Glu) of the 2-receptor, as well as position 19 (Cys to Arg) of the upstream peptide appear to confer altered capacity for receptor downregulation and expression (7). Clinical studies have also provided evidence both in healthy volunteers (8–10) and in patients with asthma (11, 12) that acute in vivo responses to -agonist (10, 11), as well as the capacity to develop receptor desensitization (9), are modified in relation to ADRB2 genotype. Further, there is a growing body of evidence that ADRB2 genotype (position 16) is a marker for adverse clinical outcomes with chronic 2-agonist exposure (13, 14).

Unfortunately, it has been difficult to establish consistent relationships between in vitro and in vivo data. The reasons for this are complex, but at least two appear important. First, there is the issue of "endogenous downregulation" (1). Paradoxically, for reasons determined by genotype, the acute response to pharmacologic concentrations of 2-agonist in vivo may be greatest in patients harboring receptors that are theoretically resistant to downregulation with exposure to physiologic concentrations of endogenous catecholamine (15). This may explain why, in vivo, acute responses are greater in Arg-16 homozygotes (11, 12), whereas the same genotype predisposes to adverse outcomes, possibly resulting from enhanced pharmacologically induced downregulation during long-term -agonist exposure (13, 14). Second, because of linkage disequilibrium, the distribution of SNPs is not random. Rather, particular combinations of SNPs (haplotypes) occur, and these may be of more importance in determining the clinical phenotype, particularly if each SNP has a functional role and where one SNP operates in an opposite direction to the other (16). Against this background, Drysdale and colleagues have described the common haplotypes of ADRB2, comprising a relatively small number of combinations of SNPs (17).

A significant relationship between ADRB2 haplotype and the acute response to 2-agonist has been reported, but remains unclear (17). In the present study, our aim was to confirm that there are consistent between-haplotype differences in the response to single doses of inhaled albuterol in patients with asthma. Given the importance of pharmacologic tolerance in relation to our study question, we rigorously sought to minimize any confounding influence of current asthma treatment by withdrawing both inhaled corticosteroid and 2-agonist therapy before patient assessment.

Some of the data contained in this manuscript have been reported in an earlier abstract (18).

	METHODS

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The study was conducted in the course of assessing patients for a larger clinical trial. Primary care patients with doctor-diagnosed mild to moderate bronchial asthma treated for 6 months or longer, of whom nearly 80% were taking regular inhaled corticosteroid, were invited to participate. Current smokers and ex-smokers with a cumulative consumption of greater than 10 pack years were excluded. At the first study visit, a 10 ml venous blood sample was obtained and, after DNA extraction, ADRB2 haplotype was determined using previously described methods (19) and classified according to Drysdale and colleagues (17). The nonsynonymous polymorphisms comprising the common haplotypes were as follows: Arg-BUP19, Gly-16, Glu-27, and Thr-164 (haplotype 2); Cys-BUP19, Arg-16, Gln-27, and Thr-164 (haplotype 4); Cys-BUP19, Gly-16, Gln-27, and Thr-164 (haplotype 6); and Cys-BUP19, Gly-16, Gln-27, and Ile-164 (haplotype 7). Patients harboring the 2/2, 2/4, 2/6, 4/4, 4/6, 6/6, and X/7 haplotypes (where X was 2, 4, or 6) continued in the study, but those with rarer or indeterminate haplotypes were withdrawn. The investigators undertaking the clinical component of the study remained blinded to haplotype data.

Before bronchodilator response measurement, all 2-agonist and inhaled corticosteroid treatment was withdrawn in a sequential manner. Long- and short-acting 2-agonists were withdrawn at the first study visit to allow reversal of any downregulation resulting from regular 2-agonist exposure. Each patient was provided with a substitute "reliever" inhaler containing 20 µg/puff ipratropium (Atrovent; Boehringer, Ingelheim, Germany). They also received an inhaler containing albuterol (Ventolin; GlaxoSmithKline, Greenford, UK) strictly for emergency use, a supply of 20 mg prednisone tablets, and a personalized action plan to guide the use of these drugs in the event of deteriorating asthma. After 2 weeks (or earlier, if necessary), patients attended for further assessment. Those unable to tolerate 2-agonist withdrawal were excluded from the study. Those who tolerated 2-agonist withdrawal and who were not taking inhaled corticosteroid therapy underwent the bronchodilator response test.

For those patients taking inhaled corticosteroid, this treatment was discontinued for 3 weeks before bronchodilator response was assessed. During this period, patients monitored their symptoms and peak flows twice daily, and were telephoned by an investigator every 3 days. They continued to refrain from all 2-agonist use. Predetermined individualized criteria, based on peak flow and symptoms, were set to determine "unacceptable deterioration." If this occurred before 3 weeks, then patients were instructed to contact the researchers promptly, and their bronchodilator response was measured. Where albuterol use was unavoidable for reasons of safety, patients were withdrawn if 2-agonist use had occurred on more than one single occasion. If used on one occasion only, then spirometric measurements were delayed for at least 6 hours. Patients had 24-hour access to study investigators. The protocol for 2-agonist and inhaled steroid withdrawal has been safely undertaken previously by the investigators (20).

Bronchodilator response was measured by spirometry before and 20 minutes after a single dose of inhaled albuterol (2.5 mg. given via nebulizer). Spirometers were calibrated before use. Three acceptable tests using American Thoracic Society criteria (21) were obtained; each measurement of FEV₁ and FVC was reproducible to within 100 ml.

The study protocol was approved by the Otago and Canterbury Ethics Committees, and each participant gave written, informed consent.

Statistical Analyses
No power calculation was undertaken a priori, given that the reported data were derived from a study that had another primary outcome. Bronchodilator response was calculated as the percent change in FEV₁ from baseline. It was further classified as "positive" if the percent change was 12% or greater and a minimum of 200 ml. The effects of ADRB2 haplotype and genotype were determined by analysis of covariance using baseline FEV₁ as the covariate.

	RESULTS

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A total of 176 patients entered the study, 15 of whom had either an indeterminate haplotype or a rare combination and were excluded. The remaining 161 patients harbored the 2/2 (n = 35, 21.7%), 2/4 (n = 51, 31.7%), 2/6 (n = 25, 15.5%), 4/4 (n = 23, 14.3%), 4/6 (n = 22, 13.7%), and 6/6 or X/7 ("other"; n = 5, 3.1%) ADRB2 combinations, respectively. The distribution of haplotypes was found to be in Hardy-Weinberg equilibrium when analyzed using Arlequin software (Department of Anthropology, University of Geneva, Geneva, Switzerland [22]), with haplotypes treated as multiple alleles at a single locus. The demographic data for the study population are shown in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Demographic and clinical data for 161 subjects who were entered into the study and who harbored one of the six most common 2-ADRENOCEPTOR haplotypes

The mean % change in FEV₁ after single doses of albuterol ranged from 11.6% (SD = 8.2) for 2/4 subjects to 16.0% (SD = 10.6) for 2/2 subjects. The results are shown in Figure 1. There were no significant differences between haplotype groups by analysis of covariance (p = 0.21). There was no evidence that haplotype groups 2/2 and 4/4 consistently had the lowest and highest bronchodilator responses. When bronchodilator response was defined as an improvement in FEV₁ of 12% or greater, the percentage of patients with a positive response was 52, 41, 48, 48, and 37% for 2/2, 2/4, 2/6, 4/4, and 4/6 haplotype groups, respectively (not significant).

View larger version (11K): [in this window] [in a new window]   Figure 1. Mean changes in FEV1 (%) 20 minutes after a single dose of inhaled albuterol in 138 patients with mild to moderate asthma. The group is stratified by 2-adrenoceptor haplotype: 2/2, 2/4, 2/6, 4/4, and 4/6. Bars represent 1 SEM.

	DISCUSSION

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The results of the present study have failed to confirm a significant and consistent relationship between ADRB2 haplotype and the magnitude of response to a single inhalation of albuterol. This was true whether that response was assessed linearly (% increase in FEV₁) or categorically (> or < 12% improvement in FEV₁). Our results contrast significantly with those reported by Drysdale and colleagues (17), despite the fact that the distribution of haplotype pairs was very similar in both study populations. Drysdale and coworkers reported a statistically significant reduction in bronchodilator responsiveness in patients harboring the 4/4 haplotype. The direction of this difference also contrasts with the results of previous studies (11, 12), comprised of patients who were homozygous at position 16 of the ADRB2 (corresponding to the 4/4 haplotype). In these earlier studies (11, 12), bronchodilator response in Arg-16 homozygotes was increased.

We also compared patients in our study who were homozygous for the Arg-16 and Gly-16 genotypes (the genotype that has been featured most frequently in the literature [11–13, 23]). These additional analyses also failed to confirm a significant relationship between genotype and bronchodilator response. Thus, whether comparisons were made by haplotype or only for selected single polymorphisms, we are unable to confirm a clear-cut relationship between genotype/haplotype and bronchodilator response.

The reasons for the apparent discrepancy between the present results and those reported previously may be related to issues of subject selection and study protocol. Drysdale and colleagues (17) studied a group of subjects with asthma for whom the inclusion criteria already included a positive bronchodilator response (see also Reference 24) Arguably, excluding subjects who failed to demonstrate bronchodilator response may have led to selection bias with respect to the primary end-point. Any definition of asthma that includes "reversible airflow obstruction" is obviously problematic in this regard, and for this reason we included patients with "doctor-diagnosed" rather than spirometrically defined asthma.

Another important issue is the effect of prior drug use on bronchodilator response. Given that the functional consequences of genetic variation of ADRB2 theoretically include differences in predisposition to receptor downregulation, current treatment with 2-agonists may be important. In previous studies (11, 12, 17), prior exposure to 2-agonist treatment was permitted. Arguably, if a particular haplotype is associated with the development of greater degrees of bronchodilator tolerance, then current treatment with 2-agonist may have a confounding effect on the measured relationship between genotype/haplotype and bronchodilation after single doses of 2-agonist. Recent data provide supportive evidence that airway function is significantly altered in relation to ADRB2 genotype, depending on whether regular 2-agonist treatment has recently been started or stopped (13). Inhaled corticosteroid treatment may also have an influence. By reducing bronchial hyperresponsiveness and improving airway opening, inhaled corticosteroid therapy may reduce the available response to bronchodilator and confound the overall results. Ideally, for these reasons, treatment-naive subjects should be studied. In practice, however, this is not feasible, but these problems provided the rationale for our treatment-withdrawal protocol.

More recent studies report inconsistent relationships between ADRB2 genotype/haplotype and bronchodilator response. In the report by Silverman and colleagues (25), a significant relationship was found for a single synonymous polymorphism (at nucleotide 523), which has hitherto been unreported. For associated haplotypes, the pattern of relationship to bronchodilator response was in fact opposite to that reported by Drysdale and colleagues (17). In contrast, although in the Genetics of Asthma in Latino Americans study (23) the impact of ADRB2 genotype/haplotype was similar to that reported previously (11, 12) (i.e., subjects harboring the Arg-16 moiety demonstrated enhanced bronchodilator response), this was limited to certain ethnic groups (i.e., Puerto Ricans, but not Mexicans). Also this relationship was observed only in subjects whose asthma was characterized by a prebronchodilator FEV₁ of less than 80% predicted. In both studies (23, 25), no attempts were made to withdraw 2-agonist treatment before the albuterol challenge, again raising the possibility that the overall inconsistencies (in relation to ethnicity or asthma phenotype) may have been due to confounding by preexisting pharmacologic tolerance. In our own study population, comprised only of New Zealanders of European descent, ethnic background is unlikely to be a reason for our negative findings. Likewise there were no important differences in the severity of airflow obstruction between the present study population and those studied by Choudhry and colleagues (23), which might account for our negative results.

In the recently published study by Israel and colleagues (13), regular inhaled albuterol was associated with impaired lung function in patients harboring the Arg-16 genotype. Similarly, asthma exacerbation rates were increased with regular albuterol compared with "as-required" use in the same genotype group (14). The relevance of ADRB2 haplotypes, rather than SNPs, has not been assessed in these long-term studies. Clearly, the absence of a relationship between ADRB2 genotype/haplotype and acute changes in airway opening with 2-agonist reported in this and other studies (26) does not preclude the potential importance of ADRB2 pharmacogenetics in determining outcomes when 2-agonist drugs are administered regularly (27).

	FOOTNOTES

 
Supported by a grant from the Health Research Council of New Zealand. A.D.S. and S.I. were GlaxoSmithKline Research Fellows, and received an unrestricted educational grant from GlaxoSmithKline during the conduct of the study.

Conflict of Interest Statement: D.R.T. has received a research grant from GlaxoSmithKline, and has acted as an expert witness on behalf of AstraZeneca; M.J.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.A.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.D.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.I. received an educational grant of $40,000 (NZ) per annum for 2 years (2001–2003) from GlaxoSmithKline; A.L.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.D.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.O.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.P.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.P.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.P.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 20, 2005; accepted in final form May 9, 2005

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This Article Abstract Full Text (PDF) All Versions of this Article: 200501-092OCv1 172/6/700    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Taylor, D. R. Articles by Herbison, G. P. Search for Related Content PubMed PubMed Citation Articles by Taylor, D. R. Articles by Herbison, G. P.