Abstract
BackgroundGenome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.MethodsUsing genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.ResultsTwenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.ConclusionsThrough GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.
Highlights
Two major classes of leukotriene modifiers, including leukotriene antagonists and lipoxygenase inhibitors, are commonly prescribed for management of asthma symptoms
Through Genome-wide association study (GWAS), we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics
Definition of abbreviations: N = number of subjects providing DNA samples evaluated in this study; SD = standard deviation; FEV1 = forced expiratory volume in 1 second; Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) = Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol Trial; LODO = Effectiveness of Low Dose Theophylline as Add On Therapy for the Treatment of Asthma; CLIC = Characterizing the Response to a LT Receptor Antagonist and Inhaled Corticosteroid trial; PACT = Pediatric Asthma Controller Trial
Summary
Two major classes of leukotriene modifiers, including leukotriene antagonists (e.g. montelukast) and lipoxygenase inhibitors (zileuton), are commonly prescribed for management of asthma symptoms. As with all asthma medications, therapeutic responses to montelukast are highly variable, with some patients responding preferentially to leukotriene modifiers vs other medications, such as inhaled corticosteroids [9,10,11]. 40–50% of patients do not respond to this class of medication and require additional therapeutic intervention [12]. Evidence for genetic associations with montelukast treatment response are available only from candidate gene studies, and additional pharmacogenetic loci for montelukast likely remain undiscovered. Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics
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