The Pharmacogenetics of Asthma: a Candidate Gene Approach

The Pharmacogenomics Journal (2001) 1, 27–37 2001 Nature Publishing Group All rights reserved 1470-269X/01 $15.00 www.nature.com/tpj CLINICAL IMPLICATION to more effectively treat this syndrome The pharmacogenetics of asthma: a would be of great benefit. While much is known about the candidate gene approach pathobiology of asthma and the inflammatory mediators and effector ES Silverman1, SB Liggett2, EW Gelfand3, LJ Rosenwasser3, cells that produce the clinical pheno- RM Baron1, S Bolk4, ST Weiss1 and JM Drazen1 type, the genetic and environmental causes of the disease have remained 5 1Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and obscure (reviewed in Kay, and 6 Harvard Medical School, Boston, MA; 2Department of Medicine, University of Cincinnati Holgate ). Although a small percent- College of Medicine, Cincinnati, OH; 3Departments of Medicine and Pediatrics, National age of asthma cases may result from a Jewish Medical and Research Center, University of Colorado Health Sciences Center, single environmental or genetic cause, Denver, CO; 4Whitehead Institute for Genome Research, Massachusetts Institute of most cases result from the interaction Technology, Boston, MA, USA of multiple genetic and environmental factors. Each of these factors acting alone would be expected to contribute INTRODUCTION describe a candidate gene approach a small amount to the development of Asthma is a common respiratory syn- that is being used to uncover asthma. However, when combined drome characterized by partially additional polymorphisms with phar- with other factors, the ultimate reversible airflow obstruction, airway macogenetic potential. phenotype or a particular character- hyperresponsiveness, and airway istic of an individual’s phenotype, inflammation. The syndrome is caused such as atopy, severity, or response to by a complex interaction between gen- ASTHMA AND ITS TREATMENT a drug is established. Moreover, since etic and environmental factors that Asthma is a clinical syndrome with asthma is a syndrome reflecting many results in a spectrum of biologic and three defining characteristics: (1) pathophysiologic pathways, it is likely clinical features. Among the spectrum recurrent episodes of airway obstruc- that different sets of genes and of features is a highly variable response tion that resolve either spontaneously environmental factors lead to asthma to asthma therapeutics. There are cur- or as a result of therapy; (2) increased or a particular phenotype in different rently three major classes of asthma airway hyperresponsiveness, which is patients or populations. Thus, therapeutics available: (1) beta2-agon- an increased bronchoconstrictor although several studies based on link- ists (␤-agonist); (2) glucocorticoids response to stimuli that would have age analysis have defined genomic (GC); and (3) inhibitors of the little or no effect in nonasthmatic sub- regions of interest, it should come as cysteinyl-leukotriene pathway (cLI). jects; and (3) chronic airway inflam- no surprise that a single ‘asthma gene’ Asthmatic patients vary greatly in mation, often with abundant eosino- 7,8 their response to all three classes of phils.1–3 Asthma severity is usually has not been identified. Neverthe- drugs and it is estimated that up to 60– measured by the presence or absence less, these genome-wide searches for 80% of this variability may have a of symptoms, the frequency of exacer- linkage have consistently identified pharmacogenetic basis. Over the past bations, and the degree of airflow important chromosomal regions that 10 years, several polymorphic loci resistance as measured by the forced have highlighted known genes as have been discovered in genes that expiratory volume in one second being good ‘asthma candidates’ with the potential to contribute to the play a role in the action of these drugs. (FEV1). As a clinical problem, asthma Data suggest that these polymor- is both prevalent and associated with asthma phenotype if a particular allele phisms directly or indirectly alter an substantial morbidity. There are is present in an individual. asthmatic’s response to therapy and approximately 17 million asthmatic At the cellular level, eosinophils, can be used to predict the response to patients in the United States (6% of mast cells, alveolar macrophages, lym- certain asthma drugs, thereby maxim- the adult population), and asthma is phocytes and neutrophils recruited to izing efficacy and avoiding adverse the number one cause of hospitaliza- the airways of asthmatics produce a effects. It is likely that many, as yet tions and emergency room visits for variety of inflammatory mediators, undiscovered, polymorphisms exist children. The health care costs such as histamine, kinins, neuropep- given the large number of gene pro- approximate 8 billion dollars per year tides, and leukotrienes, which lead to ducts involved in the pharmacodyn- of which 35–40% are due to medi- bronchial smooth muscle constriction amic and pharmacokinetic pathways cation costs. Moreover, the problem and obstruction of airflow, and the of all three classes of asthma drugs. In has been getting worse with a world- perpetuation of airway inflam- this review we discuss the established wide increase in prevalence of 30% mation.9,10 An understanding of the asthma pharmacogenetic loci and over the two past decades.4 Strategies inflammatory processes and the mol- Asthma pharmacogenetics ES Silverman et al 28 ecular pathways of these mediators has led to the development and wide- spread use of several pharmacologic agents that mitigate airway inflammation and bronchoconstriction. Three major classes of asthma therapeutics are currently in use: (1) ␤-agonist (eg albuterol, salmeterol, fenoterol); (2) GC (eg, beclomethasone, triam- cinolone, prednisone); and (3) cLI (eg, montelukast, zafirlukast, zileuton). In the early 1990s, a classification scheme was developed for defining asthma severity and choosing appropriate regi- mens from among these classes of drugs.2 Reliever drugs (inhaled, short acting ␤-agonist) are usually adequate for mild intermittent asthma and pro- vide rapid ‘rescue’ for acute airway obstruction when it infrequently occurs. In contrast, Controller drugs (inhaled GC, long acting ␤-agonist, Ϯ Figure 1 Mean percentage change from baseline ( SE) in FEV1 over the 12-week treat- and cLI) are necessary for mild, moder- ment period. Black squares represent patients receiving inhaled beclomethasone, 200 ␮g ate or severe persistent asthma in twice daily; white triangles represent patients receiving montelukast, 10 mg once daily; addition to reliever drugs, because and black circles represent patients receiving placebo. Beclomethasone increased mean they modify the airway environment, FEV1 approximately 13.1% at 12 weeks, whereas montelukast increased mean FEV1 and lessen the frequency of acute air- approximately 7.4%. Modified from Malmstrom et al.11 way narrowing in the more sympto- matic patients. When asthmatics are treated according to these established the montelukast group11 (Figure 1). lations based on the Repeatability (r) guidelines, the vast majority of However, when these same data are of the treatment response for all three patients can be effectively managed viewed from a different perspective, classes of asthma drugs, defined as the with minimal morbidity, whether it is focusing on the number of individuals fraction of the total population vari- directly related to asthma or indirectly as a function of percent change in ance which results from among indi- caused by drug toxicity. However, FEV1 from baseline, it is clear that vidual differences, shows values for r there is an important caveat that must many patients had little response. In between 60–80% indicating the upper be considered with this statement— fact, several patients appear to have limit of the genetic component and not all asthmatics are the same and had an adverse response to treatment suggests that a substantial fraction of there is tremendous heterogeneity in with a decline in FEV1 at 12 weeks the variance of the treatment response therapeutic response to each asthma compared with baseline (Figure 2). The could be genetic in nature.12 The ulti- drug. increase in mean FEV1 for all patients mate goal of asthma pharmacogenet- is eschewed by a dramatic increase in a ics is to identify this genetic infor- HETEROGENEITY OF few individuals. Furthermore, a careful mation and use it to tailor an THERAPEUTIC RESPONSE analysis of these studies indicates that individual’s therapeutic regimen in Although all three classes of asthma individuals responsive to one class of order to maximize efficacy and minim- drugs are effective when examined in asthma drug may not necessarily be ize side effects. large clinical drug trials, many studies the individuals responsive to a differ- indicate that there is wide latitude ent class of asthma drug. These types Asthma Pharmacogenetics in inter-individual response. For of data illustrating variable drug effi- Obviously, sequence variants that lead example, in a study by Malmstrom et cacy are not limited to asthma drug to the identification of novel meta- al comparing the efficacy of the leuko- trials but can be found for almost all bolic pathways or novel mechanisms triene antagonist montelukast (10 mg classes of drugs. The degree to which for inflammation would have great a day) with the inhaled steroid beclo- this inter-individual variability is gen- potential for the development of new methasone (200 ␮g twice a day), it is etic remains uncertain

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