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Genome-Wide Association Study of Leukotriene Modifier Response In OPEN The Pharmacogenomics Journal (2016) 16, 151–157 © 2016 Macmillan Publishers Limited All rights reserved 1470-269X/16 www.nature.com/tpj ORIGINAL ARTICLE Genome-wide association study of leukotriene modifier response in asthma A Dahlin1, A Litonjua1,2, CG Irvin3, SP Peters4, JJ Lima5, M Kubo6, M Tamari6 and KG Tantisira1,2 Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N = 526) of zileuton response were interrogated. Using a gene–environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery +replication), rs12436663 in MRPP3 achieved genome-wide significance (P = 6.28 × 10 − 08); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P = 1.25 × 10 − 07). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs. The Pharmacogenomics Journal (2016) 16, 151–157; doi:10.1038/tpj.2015.34; published online 2 June 2015 INTRODUCTION improved response to LTMs; in addition, regulatory variants in The leukotriene pathway is an important therapeutic target for CYSLT2 (but not CYSLT1) that were significantly associated with asthma therapy. Leukotriene-modifying agents (LTMs) improve increased morning peak expiratory flow in patients taking 9–12 asthma by either selectively preventing leukotriene production montelukast were identified. SNPs associated with LTM from arachidonic acid via 5-lipoxygenase (5-LO) inhibition (e.g., plasma levels and differential responsiveness to LTMs have also zileuton), or by preventing leukotrienes from binding to the been reported for solute carrier organic anion transporter 9,10,13,14 major cysteinyl leukotriene receptor, CysLT1 (e.g., montelukast, family, member 2B1 (SLCO2B1) and ABCC1. Importantly, pranlukast and zarfirlukast).1–3 LTMs are effective in improving we have previously demonstrated that variants in multiple lung function, asthma symptoms and quality of life in patients genes contribute to the response of both leukotriene inhibitors with asthma and allergic rhinitis by reducing airway hyper- (e.g., zileuton) and leukotriene receptor antagonists (e.g., responsiveness and eosinophilia.4–6 montelukast).11 Despite their general efficacy, patient responses to LTMs are not Although the initial results of these candidate gene studies are consistent, with some individuals failing to respond to promising, replication of identified associations has been proble- treatment.7–9 The presence of significant inter-individual varia- matic, making it difficult to estimate the degree of contribution of bility in the treatment response to LTMs suggests that variation in individual genes to LTM response. By necessity, candidate gene patient genetics may underlie this phenomenon.7–11 Historically, studies focus on characterizing the genotype–phenotype relation- variable response to leukotriene inhibition formed the basis for ships within individual genes that are chosen a priori based on the first reported asthma pharmacogenetic study.7 In an effort to biological and clinical information, rather than an agnostic characterize this pharmacogenetic relationship, researchers initi- approach that considers data from the entire genome. Recent ally focused on candidate genes within pharmacological pathways genome-wide association studies (GWASs) of symptomatic for LTM response, including arachidonate 5-lipoxygenase (ALOX5), response to asthma medications have identified multiple genes the gene encoding 5-LO, in addition to ATP-binding cassette, sub- associated with patient responsiveness to inhaled corticosteroids, family C (CFTR/MRP), member 1 (ABCC1),9,11 cysteinyl leukotriene adding to the growing evidence for a genetic basis for therapeutic – receptor 1 (CYSLTR1),9,11,12 cysteinyl leukotriene receptor 2 efficacy in asthma patients.15 17 Limited information from (CYSLTR2),9,11,12 leukotriene A4 hydrolase (LTA4H),9–12 leukotriene candidate gene studies of zileuton and montelukast response C4 synthase (LTC4S)9–12 and others. Studies of ALOX5 have indicates that patient genetics has a role in LTM response; identified multiple single-nucleotide polymorphism (SNP) associa- however, to date, no genome-wide investigation of LTM response tions with symptomatic improvement and changes in measures of has been reported. For these reasons, we performed a GWAS to lung function during LTM therapy.7,9–12 Two studies of the LTC4S identify novel genetic loci associated with leukotriene modifier gene identified promoter and intronic SNPs associated with response in asthmatic patients. 1Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; 2Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; 3Department of Medicine, University of Vermont, Burlington, VT, USA; 4Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; 5Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, Jacksonville, FL, USA and 6Center for Integrative Medical Sciences, Riken, Yokohama, Japan. Correspondence: Dr A Dahlin, Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA. E-mail: [email protected] Received 20 August 2014; revised 19 November 2014; accepted 28 January 2015; published online 2 June 2015 GWAS of zileuton and montelukast response A Dahlin et al 152 MATERIALS AND METHODS usual treatment regimens these patients received while they were being Overview of study populations treated by their primary care providers). For all patients, this could include treatment regimens including, but not limited to, theophylline, over 6 The discovery and replication cohorts evaluated in this study consisted months.19 The study population included 926 nonsmoking males and of 526 adult patients with moderate, persistent asthma from two females, aged 12 years and older, who had not taken any investigational independent, placebo-controlled clinical trials (conducted by Abbott, drugs and who demonstrated an FEV of at least 40% of predicted when Chicago, IL, USA)18,19 evaluating the efficacy of a controlled-release (CR) 1 taken 48 h or more after the last theophylline administration and at least formulation of zileuton. The primary GWAS cohort (‘Abbott trial 1’) 12 h following long-acting β-agonist use and at least 6 h following short- included 160 patients randomized to receive zileuton and 144 patients acting β-agonist use, and demonstrated a 15% or greater increase in FEV randomized to receive placebo for 12 weeks (details of the trial are 1 18 following inhaled albuterol, or reported a history of 15% reversibility within provided in Nelson et al. ). Replication of initial GWAS results was 19 performed in a cohort of 149 patients randomized to receive zileuton and 1 year before entering into the study. Patients were randomized to 73 patients receiving placebo for 12 weeks (‘Abbott trial 2’), as adjunctive zileuton CR plus usual care, or placebo plus usual care, in a 2:1 ratio, and therapy to usual care (details of the trial are provided in Wenzel et al.19). To were evaluated over 6 months. Both white (85.7%) and non-white (14.3%) evaluate potential overlap between genetic predisposition to zileuton and subjects were evaluated in this study. Although 926 subjects were included montelukast responses, additional replications were performed using in the clinical population, for the GWAS, complete genome-wide genotype two clinical trials of montelukast response, which were previously data were available from 149 patients randomized to receive zileuton and fi described,20,21 the American Lung Association Asthma Clinical Research 73 patients receiving placebo. In this study, data from the rst 12 weeks Center (ALA-ACRC) trials: the Leukotriene Modifier Or Corticosteroid or following randomization to zileuton or placebo were investigated. This Corticosteroid-Salmeterol trial (LOCCS) and Effectiveness of Low Dose population was used to replicate the results from the discovery GWAS. Theophylline as Add On Therapy for the Treatment of Asthma (LODO). All Although both primary and replication cohorts contained comparable studies were approved by the institutional review boards of their numbers of white subjects, and had patients of similar mean age, the corresponding institutions, and all participants provided informed consent discovery cohort included a greater proportion of females (48% for Abbott for genetic studies. Demographic characteristics of the cohorts evaluated trial 1 vs 32.4% for Abbott trial 2). In addition, the discovery cohort patients in this study are shown in Table 1. Each cohort is described in detail below. showed a modestly greater mean % change in FEV1 following 12-week zileuton administration (Table 1). Although
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