Pharmacogenetics of Β2-Agonists

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provided by Elsevier - Publisher Connector Allergology International. 2011;60:239-246 ! DOI: 10.2332 allergolint.11-RAI-0317 REVIEW ARTICLE

Pharmacogenetics of "2-Agonists

Nobuyuki Hizawa1

ABSTRACT Short-acting β2-agonists (SABAs) and long-acting β2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the β2 adrenoceptor gene (ADRB2). This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled β2-agonists. By assess- ing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of β2-agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy.

KEY WORDS asthma, beta-2 adrenergic receptor, chronic obstructive pulmonary disease (COPD), genetic polymorphism

mizing bronchodilator therapy in patients with INTRODUCTION asthma or COPD. Much of the interest in genetic Beta-adrenergic receptors are important drug targets control of the airway responses to β-agonists has fo- in asthma and COPD. Inhaled β-receptor agonists re- cusedontheADRB2 gene; some ADRB2 polymor- main among the mostly commonly prescribed medi- phisms result in changes in the amino acid sequence cations to treat airflow obstruction in adults. How- of the β2AR, leading to alterations of its properties, ever, persistent stimulation of β2-adrenergic receptor possibly representing a risk factor for adverse re- (β2AR) pathways may have deleterious conse- sponses to β-agonist therapy.4-6 This review discusses quences, particularly in patients with asthma. Re- the current understanding of the association of cently, long-term use of β-agonists has been linked to ADRB2 polymorphisms with bronchodilator and an increased rate of deaths due to asthma.1 Data from bronchoprotective responses to chronic inhaled β2- a large placebo-controlled US study (the SMART agonists. In the future, translation of this knowledge study2;) showed a small but significant increase in into clinical guidelines for β2-agonist prescription asthma-related deaths in patients receiving sal- may contribute to improvement in the efficacy and meterol (13 deaths out of 13176 patients treated for safety of treatment for asthma and COPD. 28 weeks) versus placebo (3 deaths out of 13179 patients). As a result, the US Food and Drug Admini- ADVERSE EFFECTS OF β2-AGONISTS AND stration has recently issued recommendations on THEIR POTENTIAL MECHANISMS how long-acting β2-agonists (LABAs) should be used Despite the ability of β-agonists to cause immediate to treat asthma, placing a safety warning on LABAs reversal of airway narrowing, concern remains that used alone or in combination with inhaled corticoster- regular use of these drugs may be associated with ad- oids (ICS).3 verse outcomes especially when used to treat patients Pharmacogenetics could be a useful means of opti- with asthma. In animal models of asthma, administra-

1Department of Pulmonary Medicine, Institute of Clinical Medicine, Tsukuba, Tennodai 1−1−1 Tsukuba, Ibaraki 305−8575, Japan. University of Tsukuba, Tsukuba, Japan. Email: [email protected] Correspondence: Nobuyuki Hizawa, MD, Department of Pulmo- Received 17 March 2011. nary Medicine, Institute of Clinical Medicine, University of !2011 Japanese Society of Allergology

Allergology International Vol 60, No3, 2011 www.jsaweb.jp! 239 Hizawa N tion of β-agonists induced airway morphologic bronchomotor reactivity by means other than direct changes and bronchial hyperresponsiveness.7,8 In hu- dilatation. Chronic administration of β-blockers also man studies, regularly scheduled use of inhaled β- attenuated airway responsiveness and eosinophilic in- agonists has resulted in loss of asthma control, de- flammation both in a murine model of asthma34 and clines in morning peak flow, longer durations of in patients with asthma,35 suggesting that persistent asthma exacerbations, rebound airway hyperrespon- activity of the airway β2AR negatively impacts in- siveness (AHR),9-15 and airway inflammation.16,17 Epi- creased airway inflammation and remodeling in demiological studies have demonstrated a positive asthma. An animal study also showed that β2AR sig- correlation between the chronic use of short-acting naling is required for development of mucin produc- β2-agonists and asthma mortality.18,19 Recently, a tion, airway hyperresponsiveness, and inflammatory large trial with the long-acting β2-agonist, salmeterol, cellular infiltrates in a murine model of asthma.36 was stopped because of increased death rates and se- Continuous use of β-agonists as asthma monotherapy rious “asthma related” events among the African also has the potential to increase type 2 cytokine- American subgroup on long-term salmeterol.2 mediated airway inflammation.37,38 β2-Agonists also The potential mechanisms for higher risk of death significantly enhanced the cytokine-induced TSLP and life-threatening adverse effects are unclear but production by primary human lung tissue cells.39 In- may include masking increasing inflammation and terestingly, an increased risk of severe exacerbation delaying awareness of worsening asthma.20 The com- of respiratory symptoms as well as death in some pa- mon explanation for these observations is that the ad- tients using LABAs has been reported only for the verse effects of regular β-agonist therapy are related treatment of asthma but not for COPD. This may indi- to desensitization of the β2AR,10,11,13,21-23 a character- cate that β2AR agonism on airway hyperresponsive- istic of many membrane-associated receptors after ness and allergic inflammation rather than agonist- high-dose or repeated exposure to agonists. “Endoge- induced receptor downregulation represents a very nous downregulation” is an issue.24 Paradoxically, for probable mechanism of the adverse effects associated reasons determined by genotype, the acute response with long-term β2-agonists therapy. to pharmacologic concentrations of β2-agonists in vivo may be greatest in patients harboring receptors ADRB2 GENE POLYMORPHISMS that are theoretically resistant to downregulation with The ADRB2 gene is a small intronless gene on chro- exposure to physiologic concentrations of endoge- mosome 5q31-q32,40 a region that is genetically nous catecholamine.25 This may explain why acute re- linked to asthma and related phenotypes.41,42 Reihaus sponses in vivo are greater in individuals homozy- et al.43 originally described 9 coding polymorphisms gous for Arg16,26,27 whereas the same genotype pre- in ADRB2, 4 of which (Gly16Arg, Gln27Glu, Val34 disposes to adverse outcomes, possibly resulting Met, and Thr164Ile) create nonsynonymous changes from enhanced pharmacologically induced down- in the amino acid sequence. Drysdale et al.4 de- regulation during long-term β-agonist exposure.28-30 scribed the molecular haplotypic structure of the In this regard, proinflammatory cytokines in the asth- ADRB2 gene in several ethnic groups; 13 polymor- matic condition known to cause heterologous desen- phisms were organized into 12 haplotypes out of the sitization of the β2AR31 might also be of importance. theoretically possible 8192 combinations, and deep Alternatively, emerging data suggest proinflamma- divergence in the distribution of some haplotypes tory effects associated with persistent β2AR activation was noted in white, black American, Asian, and resulting in increased airway inflammation and hyper- Hispanic-Latino groups with differences of more than responsiveness, cardinal features of asthma. Studies 20-fold among the frequencies of the 4 major haplo- using transgenic mice overexpressing airway smooth types. Recently, comprehensive resequencing of a muscle β2AR revealed that persistent high-level acti- 5.3-kb region of ADRB2 in 669 African American and vation of the β2AR leads to increased expression of white participants has identified 49 polymorphisms. phospholipase C-β in airway smooth muscle and may These polymorphisms are in the regulatory regions, augment the effects of bronchoconstrictors such as including the promoter region and the 3’-UTR. They acetylcholine, histamine, and leukotrienes.32 Another contribute to haplotypic structure and genetic asso- study provided evidence that prolonged exposure of ciation with asthma-related phenotypes.44 Screening cultural human airway smooth muscle cells to β2- of the ADRB2 gene in Japanese participants has also agonists auguments procontractile signaling path- revealed 15 single nucleotide polymorphisms (SNPs) ways elicited by thrombin, bradykinin and histamine. within the 3-kb promoter and 1.2-kb structural re- This study indicated repetitive β2-agonist use lead to gions.45 sensitization of excitation-contraction signaling pathways as a result of reduced expression of Regulator of FUNCTIONAL RELEVANCE OF ADRB2 GENE G protein signaling 5 (RGS5), which is an inhibitor of POLYMORPHISMS G-protein-coupled receptor (GPCR) activity.33 Thus, Functional responses in recombinant cell systems the β2AR regulates constrictive signals, affecting and primary cultured airway cell lines have revealed

240 Allergology International Vol 60, No3, 2011 www.jsaweb.jp! Pharmacogenetics of β2-Agonists altered downregulation profiles for the Arg16Gly and in participants homozygous for Gly16 has been repli- Gln27Glu variants of this receptor and altered cou- cated in other studies.53,60,61 We studied a Ban-I pling with the Thr164Ile variant.46-48 In addition, sev- RFLP and subsequently demonstrated that it coin- eral more polymorphisms have been identified in the cided with SNP +523 in 58 individuals from 4 Japa- ADRB2 5’ promoter region, one of which is localized nese families62; this variant appeared to be associated to the 5’ leader cistron (5’LC), a signaling peptide in- with bronchodilator responsiveness. The increases in volved in regulation of β2AR translation.49 In recom- FEV1 after inhalation of procaterol hydrochloride binant cells, 5’LC-Arg19Cys (allelic frequency about were also measured in 81 Japanese patients with 60% in white individuals) leads to higher β2AR ex- moderate to severe asthma (mean age of the partici- pression49 and β2AR promoter-driven luciferase activ- pants was 54 years, and 47% were smokers).63 Multi- ity50 than in wild type cells. Studies of the genetic ef- variate linear regression analysis showed that in- fects of the ADRB2 polymorphisms on agonist- creased responsiveness to procaterol was correlated induced β2AR desensitization in airway smooth mus- with the number of Arg16 alleles, indicating that the cle cells48,51 and mast cells52 in vitro andinlympho- ADRB2 Arg16Gly polymorphism was associated with cytes ex vivo53,54 have yielded conflicting results: Arg bronchodilator responsiveness to β2-agonists even in 16Gly and Gln27Glu polymorphisms have been asso- elderly asthmatic patients and smokers. ciated with both decreased and increased agonist- Drysdale et al. reported an effect of haplotype pairs induced desensitization of the β2AR-mediated cyclic on acute bronchodilator responses to albuterol.4 Re- adenosine monophosphate (cAMP) response48,51 or cent reports on patients with asthma, however, re- with downregulation of the receptor.48,52-54 ported no significant relationship between haplotype Alterations in function due to β2AR allelic vari- pairs and bronchodilator response.44,64 The study by ations might result from a combination of polymor- Choudhry et al.61 provides insight into potential eth- phisms rather than from a single polymorphism.4 nic group differences in pharmacogenetic effects (Ge- Linkage disequilibrium may account for conflicting netics of Asthma in Latino Americans [GALA] Study). results regarding the functional effects of these poly- The investigators found that in a group of 274 Mexi- morphismswhenconsideredinisolation.48,51-54 can and 393 Puerto Rican families recruited on the Haplotype may predict the clinical phenotype better, basis of having a child with asthma, the Arg16 allele particularly if each polymorphism included has a was significantly associated with increased bronchial functional role and when 1 polymorphism operates in reversibility in the combined population; however, a direction opposite to the other.55 Liggett et al.re- when stratified by ancestral country of origin, the as- cently constructed 8 common haplotypes derived sociation remained significant only in the Puerto Ri- from 26 polymorphisms. Whole-gene transfection can group. The investigators found that bronchodila- was performed with COS-7 cells and revealed 4 haplo- tor responses were greater in the group with a spe- types with increased cell surface β2AR protein ex- cific haplotype. The Childhood Asthma Management pression as compared with the others. Agonist- Program (CAMP), another large family-based study promoted downregulation of β2AR protein expression consisting primarily of participants with mild was also haplotype-dependent, and was found to be asthma,5 included genotype data on 8 ADRB2 SNPs increased for 2 haplotypes.56 in 700 complete trios (mother, father, and child with asthma). The same haplotype was associated with ADRB2 GENE POLYMORPHISMS AND RE- lower bronchodilator response measures in both the SPONSES TO β-AGONISTS CAMP participants and the GALA Puerto Rican par- A) ACUTE BRONCHODILATOR RESPONSES ticipants. These data, however, contrast with the re- The clinical response to β-agonists in the treatment of port by Drysdale et al.,4 in which the same haplotype asthma shows a high degree of interindividual vari- was associated with lower measures of bronchodila- ation that is not adequately explained by ethnicity, tor drug responsiveness. Furthermore, in the GALA age,27,57 or baseline lung function.1,58 A recent analy- study, no association was observed between Arg16 sis estimated that roughly 60% of the population vari- Gly genotypes and drug responsiveness among Mexi- ance in the forced expiratory volume in 1 second cans with asthma. These discrepancies may be partly (FEV1) response to albuterol was attributable to ge- explained by different linkage disequilibrium patterns netic variations,59 which might be caused in part by in the different study groups or by the interaction of variations in the ADRB2 gene polymorphisms. Mar- socioeconomic and other environmental factors with tinez et al.26 found that children homozygous for genetic background. Arg16 were 5.3 times more likely to show reversibility to albuterol than were those homozygous for B) REGULAR USES Gly16. Heterozygous Gly16!Arg16 children showed The genetic effects of the ADRB2 gene seem to de- intermediate responses to albuterol, whereas vari- pend on the duration of therapy, and the genetic ef- ations at the Gln27Glu polymorphism had no signifi- fects of long-term use cannot be predicted from the cant effect. A reduced response to β-agonist therapy acute effects. In an Asthma Clinical Research Net-

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p = 0.99 p = 0.0038 450 Placebo p < 0.0001 p < 0.0001 p = 0.87 p < 0.0001 Placebo Salmeterol Salmeterol 8 425 6

400 4

2 375 Mean morning PEF (L/min) 0 (geometric mean; mg/mL) 0 Arg/Arg Gly/Gly 20 Arg/Arg Gly/Gly Study group Study group PC

Fig. 1 Dissociation between bronchodilator and bronchoprotective effect of ICS/LABA. (Left) Morning PEF in patients with asthma while assigned to receive treatment with ICS plus LABA or placebo, by genotype. Adapted from Reference 69. (Right) Methacholine responsiveness in participants while assigned to receive treatment with inhaled corticosteroid plus salmeterol or placebo, by genotype. Adapted from Reference 69. work; National Heart, Lung, and Blood Institute genotype and 29 patients with Gly16!Gly16 genotype (ACRN) study,28 participants with asthma who were used them as needed. During follow-up periods of at homozygous for Arg16 and treated with regular, least 6 months at Hokkaido University Hospital, long- short-acting β-agonists experienced significant de- term bronchodilator responses were assessed using 3 clines in PEFR compared with Gly16 homozygous indices: (a) improvement in FEV1 (DeltaFEV1 [mL]), participants. Taylor et al. observed similar effects as (b) DeltaFEV1!FEV1 at the initial visit, and (c) Del- well as increased exacerbations in Arg16 homozy- taFEV1!predicted FEV1. In patients with the Gly16! gous participants on regular albuterol treatment. Gly16 genotype, those who regularly used β2- However, they did not report changes in Arg16! agonists had greater improvement in FEV1 in every Arg16 participants receiving intermittent albuterol or index (p = 0.027-0.041) than did those who used them the long-acting β-agonist salmeterol.29 The first pro- as needed. In contrast, in patients with the Arg16! spective, randomized clinical trial examining pharma- Arg16 genotype, regular usage of β2-agonists did not cogenetic responses in asthma confirmed the poorer yield greater improvement in FEV1 when compared response of Arg16!Arg16 individuals to regular short- with as-needed β2-agonist usage. This finding sug- acting β2-agonist therapy.30 In contrast, Gly16!Gly16 gests that Gly16!Gly16 and Arg16!Arg16 genotype participants receiving regular albuterol experienced responses to regular usage of β2-agonists may differ improvement in peak flow rates and fewer daily in Japanese patients with asthma. The relevance of asthma symptoms. In that study,30 the adverse effects ADRB2 haplotypes, rather than single polymor- of regular β-agonist use could be observed even phisms, was not assessed in this study. weeks after their withdrawal, at a time when β2AR de- In contrast, in a small retrospective analysis of clini- sensitization should be resolved. If regular use of β- cal trial data, no genotype-related adverse effects agonists negatively impacts the balance of factors were identified.67 In a larger retrospective study68 us- contributing to airway inflammation or airway remod- ing 2650 participants with moderate asthma, of whom eling in asthma, it could have long-term conse- 430 had the Arg16 genotype, no association between quences. This contention is supported by the fact that treatment with either salmeterol or formoterol and in studies of regular use of β-agonists adverse effects clinical outcomes was identified after stratification by have been reported only in participants homozygous ADRB2 genotype or relevant haplotypes. However, for Arg16, which is rather resistant to desensitization the patients included in both studies were prese- in vitro. lected to benefit from a long-acting bronchodilator in In addition, a report on the responses to salmeterol terms of baseline reversibility, thus perhaps exagger- in 2 ACRN trials found that Arg16!Arg16 participants ating the effect of the long-acting β-agonist in these had decreased responses to salmeterol in the pres- participants. ence or absence of concurrent ICS.65 The Arg16Gly In a prospective study in a genotype-stratified popu- polymorphism is common in the Japanese population, lation in which salmeterol was added to inhaled corti- and we retrospectively analyzed the outpatient re- costeroid therapy,69 87 mild-to-moderate asthmatic cords of asthmatic patients.66 Twenty-seven patients patients were stratified by Arg16Gly genotypes. The with the Arg16!Arg16 genotype and 35 patients with improvement in morning PEFR with salmeterol ther- the Gly16!Gly16 genotype regularly used β2- apy was similar for Arg16 and Gly16 homozygous pa- agonists, whereas 37 patients with Arg16!Arg16 tients. Half of the Arg16!Arg16 patients, however, ex-

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p = 0.09

p = 0.57 p = 0.013 480 Placebo Salmeterol 440

400

1.0 1.0 360

p = 0.027 320 Mean PEF (L/min) 0.5 p = 0.44 0.5 280 Δ FEV1 (L) Δ FEV1 (L)

0.0 0.0 0 As-needed Regular As-needed Regular Arg/Arg Gly/Gly [N = 37] [N = 27] [N = 29] [N = 35] Study group Arg/Arg Gly/Gly

Fig. 2 Infl uence of the ADRB2 genotype on bronchodilator responses to ICS/LABA both in Japanese and African American populations. (Left) Genetic infl uence of the Arg16Gly polymorphism on ΔFEV1 according to regular usage of β2-agonists in Japanese patients with asthma. Signifi cance of 0.075 was shown for the interaction between genotypes and regular use of β2 agonist. Adapted from Reference 66. (Right) Morning PEF in African-American patients with asthma while assigned to receive treatment with ICS plus LABA or placebo, by genotype. Adapted from Reference 69. perienced worsening of methacholine responsiveness during the study in a patient receiving salmeterol despite improvement in their airway function by addi- alone. Bleecker et al. also found that patients ho- tion of LABA to ICS (Fig. 1). This finding clearly indi- mozygous for Arg16 had a significantly higher num- cated the dissociation between the bronchodilator ber of disease exacerbations during the run-in phases and bronchoprotective effects of LABA, which may of the trial. underlie the significant deterioration in asthma control caused by long-term usage of LABA. In the post C) COPD hoc analysis, African American individuals with the Chronic obstructive pulmonary disease is character- Arg16!Arg16 genotype did not benefit from the addi- ized by a persistent airflow limitation that is not fully tion of LABA to ICS, which was a finding identical to reversible; however, reversibility of airflow limitations that of our previous report66 (Fig. 2). Given that in response to a bronchodilator is an important com- ADRB2 allele frequencies and genotype distributions ponent of COPD. The degree of reversibility of air- in Japanese participants were similar to those of Afri- flow obstruction shown by patients with COPD varies can Americans,4 the LARGE trial may suggest that considerably.71 In a recent study of 274 patients with patients with Arg16!Arg16 are susceptible to an in- COPD,72 we showed that bronchodilator response to creased risk of serious asthma outcomes owing to salbutamol therapy was associated with a continuous long term use of LABA. LABA therapy might pro- phenotype in patients, with a wide interindividual mote a “high level of current control” without improv- variation. We have reported preliminary evidence, in ing stability and the risk of exacerbations in patients patients with COPD, that the Arg16Gly polymor- with particular genotypes. phism has a significant physiologic role in regulating Bleecker and associates70 recently demonstrated responses to β2-agonists.73 By studying 246 patients that asthmatic patients stratified by Arg16Gly geno- with COPD who were participants in a longitudinal type showed similar clinical responses to salmeterol study of COPD (Hokkaido COPD cohort study), we alone or in combination with fluticasone. Meanwhile, compared short-term bronchodilator responses to sal- they confirmed that the use of salmeterol signifi- butamol according to ADRB2 genotypes at codons 16 cantly increases the risk of loss of asthma control, as and 27. The presence of the Arg16 allele was associ- suggested by the observation that 10 of 272 patients ated with lower bronchodilator responses to β2- receiving salmeterol alone had an exacerbation, com- agonist inhalation. Log values (postbronchodilator pared with only 1 of 272 patients receiving the ICS! FEV1-prebronchodilator FEV1) of individuals ho- LABA combination, which was statistically signifi- mozygous for Gly16 (n = 65), heterozygous for Arg16 cant. Furthermore, 1 asthma-related death occurred Gly16 (n = 106), and homozygous for Arg16 (n = 75)

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were2.19±0.43(mean±SD),2.09±0.42,and2.01± ter asthma research trial (SMART): a comparison of usual 0.42, respectively (p < 0.05). The genetic effects of the pharmacotherapy for asthma or usual pharmacotherapy Arg16Gly polymorphism were independent of the se- plus salmeterol. Chest 2006;129:15-26. verity of airflow limitation, age, and smoking status. 3. U.S. Food and Drug Administration. Information by Drug Class. Available at: http:!!www.fda.gov!drugs!DrugSafet The most common Arg16-Gln27 haplotype was also y!InformationbyDrugClass!. significantly associated with decreased bronchodila- 4. Drysdale CM, McGraw DW, Stack CB et al. Complex pro- tor responses to salbutamol (p < 0.01). Our finding in moter and coding region beta2-adrenergic receptor haplo- patients with COPD is in apparent contradiction with types alter receptor expression and predict in vivo respon- previous findings26,63 showing that asthmatic patients siveness. Proc Natl Acad Sci U S A 2000;97:10483-8. carrying Arg16 had significantly greater β2-agonist 5. Silverman EK, Kwiatkowski DJ, Sylvia JS et al. Family- responsiveness. It is possible that the mechanisms by based association analysis of beta2-adrenergic receptor which polymorphisms in the ADRB2 gene determine polymorphisms in the childhood asthma management program. J Allergy Clin Immunol 2003;112:870-6. responses to β2-agonists in patients with asthma are 6. Martinez FD. Safety of long-acting beta-agonists―an ur- different from those among patients with COPD, at gent need to clear the air. NEnglJMed2005;353:2637-9. least in part because asthma and COPD have mecha- 7. Kamachi A, Munakata M, Nasuhara Y et al. Enhancement nistic difference in their pathobiology, including dif- of goblet cell hyperplasia and airway hyperresponsive- ferent genetic and environmental backgrounds. ness by salbutamol in a rat model of atopic asthma. Tho- rax 2001;56:19-24. CONCLUSIONS 8. Tamaoki J, Tagaya E, Kawatani K, Nakata J, Endo Y, Na- Although β2-agonists are effective and safe in most gai A. Airway mucosal thickening and bronchial hyperresponsiveness induced by inhaled beta 2-agonist in mice. patients with asthma and COPD, they may be less ef- Chest 2004;126:205-12. fective or potentially harmful in some. Pharmacoge- 9. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tatters- netic approaches hold the promise of matching indi- field AE. Rebound increase in bronchial responsiveness vidualized treatments to specific genotypes in a way after treatment with inhaled terbutaline. Lancet 1988;1: that minimizes side effects while improving therapeu- 554-8. tic outcomes. From the research reported to date, 10. Cheung D, Timmers MC, Zwinderman AH, Bel EH, however, no consensus has been reached on the rela- Dijkman JH, Sterk PJ. Long-term effects of a long acting β tionship between identified ADRB2 genetic variations 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. NEnglJMed and airway responses to β2-agonists, including bron- 1992;327:1198-203. chodilation and bronchoprotective effects. Interpreta- 11. O’Connor BJ, Aikman S, Barnes PJ. Tolerance to the non- tion of the findings of genetic association studies of bronchodilator effects of inhaled beta-2 agonists in the ADRB2 polymorphisms may be complicated by asthma. NEnglJMed1992;327:1204-8. inadequate measurement of environmental exposures 12. Taylor DR, Town GI, Herbison GP et al. Asthma control such as smoking and by differences in allele and during long-term treatment with regular inhaled salbuta- haplotype frequencies of the ADRB2 gene. The com- mol and salmeterol. Thorax 1998;53:744-52. 13. Taylor DR, Sears MR, Herbison GP et al. Regular inhaled plex genotype-response effects observed limit their beta agonist in asthma: effects on exacerbations and lung clinical applications. Future large prospective studies function. Thorax 1993;48:134-8. should take account of ADRB2 haplotypic variations, 14. Sears MR, Taylor DR, Print CG et al. Regular inhaled possible gene-gene interactions, as well as gene- beta-agonist treatment in bronchial asthma. Lancet 1990; environment interactions. More insight into how al- 336:1391-6. terations in the expression or function of the gene af- 15. Drazen JM, Israel E, Boushey HA et al. Comparison of fect clinical phenotypes is necessary to help us trans- regularly scheduled with as-needed use of albuterol in late ADRB2 genetic information into application in mild asthma. Asthma Clinical Research Network. NEnglJ Med 1996;335:841-7. clinical practice. 16. Gauvreau GM, Jordana M, Watson RM, Cockroft DW, ACKNOWLEDGEMENTS O’Byrne PM. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils I’m very grateful to Mrs. Flaminia Miyamasu, an as- in asthmatic subjects. Am J Respir Crit Care Med 1997; sociate professor at Institute of Clinical Medicine, 156:1738-45. University of Tsukuba, for proofreading this paper 17. Manolitsas ND, Wang J, Devalia JL, Trigg CJ, McAulay and for her comments. AE, Davies RJ. Regular albuterol, nedocromil sodium, and bronchial inflammation in asthma. AmJRespirCritCare Med 1995;151:1925-30. REFERENCES 18. Spitzer WO, Suissa S, Ernst P et al.Theuseofbeta- 1. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. agonists and the risk of death and near death from Meta-analysis: effect of long-acting beta-agonists on se- asthma. NEnglJMed1992;326:501-6. vere asthma exacerbations and asthma-related deaths. 19. Suissa S, Ernst P, Boivin JF et al. A cohort analysis of ex- AnnInternMed2006;144:904-12. cess mortality in asthma and the use of inhaled beta- 2. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorin- agonists. Am J Respir Crit Care Med 1994;149:604-10. sky PM; SMART Study Group. The salmeterol multicen- 20. McIvor RA, Pizzichini E, Turner MO, Hussack P, Har-

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greave FE, Sears MR. Potential masking effects of sal- 37. Hung CH, Chu YT, Hua YM et al. Effects of formoterol meterol on airway inflammation in asthma. Am J Respir and salmeterol on the production of Th1- and Th2-related Crit Care Med 1998;158:924-30. chemokines by monocytes and bronchial epithelial cells. 21. Tan KS, Grove A, McLean A, Gnosspelius Y, Hall IP, Lip- Eur Respir J 2008;31:1313-21. worth BJ. Systemic corticosteriod rapidly reverses bron- 38. Loza MJ, Foster S, Peters SP, Penn RB. Interactive effects chodilator subsensitivity induced by formoterol in asth- of steroids and beta-agonists on accumulation of type 2 T matic patients. Am J Respir Crit Care Med 1997;156:28- cells. J Allergy Clin Immunol 2008;121:750.e1-5.e3. 35. 39. Futamura K, Orihara K, Hashimoto N et al.Beta2- 22. Sears MR. Is the routine use of inhaled beta-adrenergic adrenoceptor agonists enhance cytokine-induced release agonists appropriate in asthma treatment? No. Am J of thymic stromal lymphopoietin by lung tissue cells. Int Respir Crit Care Med 1995;151:600-1. Arch Allergy Immunol 2010;152:353-61. 23. Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. Beta- 40. Kobilka BK, Dixon RA, Frielle T et al. cDNA for the hu- agonist intrinsic efficacy: measurement and clinical sig- man β2-adrenergic receptor: a protein with multiple nificance. Am J Respir Crit Care Med 2002;165:1353-8. membrane-spanning domains and encoded by a gene 24. Liggett SB. Polymorphisms of the beta2-adrenergic recep- whose chromosomal location is shared with that of the re- tor. NEnglJMed2002;346:536-8. ceptor for platelet-derived growth factor. Proc Natl Acad 25. Lee DK, Bates CE, Lipworth BJ. Acute systemic effects of Sci U S A 1987;84:46-50. inhaled salbutamol in asthmatic subjects expressing com- 41. Postma DS, Bleecker ER, Amelung PJ et al. Genetic sus- mon homozygous beta2-adrenoceptor haplotypes at posi- ceptibility to asthma-bronchial hyperresponsiveness coin- tions 16 and 27. Br J Clin Pharmacol 2004;57:100-4. herited with a major gene for atopy. NEnglJMed1995; 26. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson 333:894-900. R. Association between genetic polymorphisms of the 42. Postma DS, Meyers DA, Jongepier H, Howard TD, Kop- beta2-adrenoceptor and response to albuterol in children pelman GH, Bleecker ER. Genomewide screen for pulmo- with and without a history of wheezing. JClinInvest1997; nary function in 200 families ascertained for asthma. Am J 100:3184-8. Respir Crit Care Med 2005;172:446-52. 27. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self 43. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations TH, Johnson JA. Impact of genetic polymorphisms of the inthegeneencodingfortheβ2 adrenergic receptor in beta2-adrenergic receptor on albuterol bronchodilator normal and asthmatic subjects. Am J Respir Cell Mol Biol pharmacodynamics. Clin Pharmacol Ther 1999;65:519-25. 1993;8:334-9. 28. Israel E, Drazen JM, Liggett SB et al. The effect of poly- 44. Hawkins GA, Tantisira K, Meyers DA et al. Sequence, morphisms of the beta(2) adrenergic receptor on the re- haplotype and association analysis of ADR{beta}2 in sponse to regular use of albuterol in asthma. AmJRespir multi-ethnic asthma case!control subjects. AmJRespir Crit Care Med 2000;162:75-80. Crit Care Med 2006;174:1101-9. 29. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Han- 45. Munakata M, Harada Y, Ishida T et al. Molecular-based cox RJ, Town GI. Asthma exacerbations during long term haplotype analysis of the beta 2-adrenergic receptor gene beta agonist use: influence of beta(2) adrenoceptor poly- (ADRB2) in Japanese asthmatic and non-asthmatic sub- morphism. Thorax 2000;55:762-7. jects. Allergol Int 2006;55:191-8. 30. Israel E, Chinchilli VM, Ford JG et al. Use of regularly 46. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal scheduled albuterol treatment in asthma: genotype strati- polymorphisms of the human beta 2-adrenergic receptor fied, randomized placebo-controlled cross-over trial. Lan- impart distinct agonist-promoted regulatory properties. cet 2004;364:1505-12. Biochemistry 1994;33:9414-9. 31. Laporte JD, Moore PE, Panettieri RA, Moeller W, Heyder 47. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A poly- J, Shore SA. Prostanoids mediate IL-1β-induced β- morphism of the human beta 2-adrenergic receptor adrenergic hyporesponsiveness in human airway smooth within the fourth transmembrane domain alters ligand muscle cells. AmJPhysiol1998;275:L491-501. binding and functional properties of the receptor. JBiol 32. McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett Chem 1993;268:23116-21. SB. Antithetic regulation by β-adrenergic receptors of Gq 48. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influ- receptor signaling via phospholipase C underlies the air- ence of beta 2-adrenergic receptor genotypes on signal way β-agonist paradox. JClinInvest2003;112:619-26. transduction in human airway smooth muscle cells. Am J 33. Yang Z, Cooper PR, Damera G et al. Beta-agonist associ- Respir Cell Mol Biol 1995;13:25-33. ated reduction in RGS5 expression promotes airway 49. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Poly- smooth muscle hyperresponsiveness. JBiolChem2011; morphisms of the 5’ leader cistron of the human beta2- 286:11444-55. adrenergic receptor regulate receptor expression. JClin 34. Callaerts-Vegh Z, Evans KL, Dudekula N et al. Effects of Invest 1998;102:1927-32. acute and chronic administration of beta-adrenoceptor 50. JohnattySE,AbdellatifM,ShimminL,ClarkRB,Boer- ligands on airway function in a murine model of asthma. winkle E. β2-Adrenergic receptor 5’ haplotypes influence Proc Natl Acad Sci U S A 2004;101:4948-53. promoter activity. Br J Pharmacol 2002;137:1213-6. 35. Hanania NA, Singh S, El-Wali R et al. The safety and ef- 51. Moore PE, Laporte JD, Abraham JH et al. Polymorphism fects of the beta-blocker, nadolol, in mild asthma: an of the beta(2)-adrenergic receptor gene and desensitiza- open-label pilot study. Pulm Pharmacol Ther 2008;21:134- tion in human airway smooth muscle. AmJRespirCrit 41. Care Med 2000;162:2117-24. 36. Nguyen LP, Lin R, Parra S et al. Beta2-adrenoceptor sig- 52. Chong LK, Chowdry J, Ghahramani P, Peachell PT. Influ- naling is required for the development of an asthma phe- ence of genetic polymorphisms in the β2-adrenoceptor on notype in a murine model. Proc Natl Acad Sci U S A 2009; desensitization in human lung mast cells. Pharmacogenet- 106:2435-40. ics 2000;10:153-62.

Allergology International Vol 60, No3, 2011 www.jsaweb.jp! 245 Hizawa N

53. Lipworth BJ, Hall IP, Tan S, Aziz I, Coutie W. Effects of 15:849-54. genetic polymorphism on ex vivo and in vivo function of 64. Taylor DR, Epton MJ, Kennedy MA et al. Bronchodilator β2-adrenoceptors in asthmatic patients. Chest 1999;115: response in relation to β-adrenoceptor haplotype in pa- 324-8. tients with asthma. Am J Respir Crit Care Med 2005;172: 54. Bruck H, Leineweber K, Beilfuss A et al. Genotype- 700-3. dependent time course of lymphocyte β2-adrenergic re- 65. Wechsler ME, Lehman E, Lazarus SC et al. β-Adrenergic ceptor down-regulation. Clin Pharmacol Ther 2003;74: receptor polymorphisms and response to salmeterol. Am 255-63. J Respir Crit Care Med 2006;173:519-26. 55. Judson R, Stephens JC, Windemuth A. The predictive 66. Isada A, Hizawa N, Shimizu K et al. [The Arg16Glybeta2- power of haplotypes in clinical response. Pharmacogenom- adrenergic receptor polymorphism influences long term ics 2000;1:15-26. clinical responses to beta2-agonist]. Arerugi 2008;57:713- 56. Panebra A, Wang WC, Malone MM et al. Common 21 (in Japanese). ADRB2 haplotypes derived from 26 polymorphic sites di- 67. Bleecker ER, Yancey SW, Baitinger LA et al.Salmeterol rect beta2-adrenergic receptor expression and regulation response is not affected by β2-adrenergic receptor geno- phenotypes. PLoS One 2010;5:e11819. type in subjects with persistent asthma. J Allergy Clin Im- 57. Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharma- munol 2006;118:809-16. cogenetics of asthma. Am J Respir Crit Care Med 2002; 68. Bleecker ER, Postma DS, Lawrence RM, Meyers DA, Am- 165:861-6. brose HJ, Goldman M. Effect of ADRB2 polymorphisms 58. SinDD,ManJ,SharpeH,GanWQ,ManSF.Pharma- on response to long-acting β2-agonist therapy. Lancet cological management to reduce exacerbations in adults 2007;370:2118-25. with asthma: a systematic review and meta-analysis. 69. Wechsler ME, Kunselman SJ, Chinchilli VM et al. Effect JAMA 2004;292:367-76. of [beta]2-adrenergic receptor polymorphism on re- 59. Drazen JM, Silverman EK, Lee TH. Heterogeneity of sponse to long-acting [beta]2 agonist in asthma (LARGE therapeutic responses in asthma. Br Med Bull 2000;56: trial): a genotype-stratified, randomised, placebo-contro- 1054-70. lled, crossover trial. Lancet 2009;374:1754-64. 60. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association 70. Bleecker ER, Nelson HS, Kraft M et al. Beta2-receptor between β2-adrenoceptor polymorphism and susceptibil- polymorphisms in patients receiving salmeterol with or ity to bronchodilator desensitisation in moderately severe without fluticasone propionate. Am J Respir Crit Care Med stable asthmatics. Lancet 1997;350:995-9. 2010;181:676-87. 61. Choudhry S, Ung N, Avila PC et al. Pharmacogenetic dif- 71. Calverley PM, Burge PS, Spencer S, Anderson JA, Jones ferences in response to albuterol between Puerto Ricans PW. Bronchodilator reversibility testing in chronic ob- and Mexicans with asthma. Am J Respir Crit Care Med structive pulmonary disease. Thorax 2003;58:659-64. 2005;171:563-70. 72. Makita H, Nasuhara Y, Betsuyaku T et al. Characteriza- 62. Ohe M, Munakata M, Hizawa N et al. Beta 2 adrenergic tion of phenotypes based on severity of emphysema in receptor gene restriction fragment length polymorphism chronic obstructive pulmonary disease. Thorax 2007;62: and bronchial asthma. Thorax 1995;50:353-9. 932-7. 63. Asano K, Yamada-Yamasawa W, Kudoh H et al. Associa- 73. Hizawa N, Makita H, Nasuhara Y et al. Beta2-adrenergic tion between beta-adrenoceptor gene polymorphisms and receptor genetic polymorphisms and short-term bron- relative response to beta 2-agonists and anticholinergic chodilator responses in patients with COPD. Chest 2007; drugs in Japanese asthmatic patients. Respirology 2010; 132:1485-92.

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