Genome-wide association study of leukotriene modifier response in asthma

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Genome-wide association study of leukotriene modifier response in asthma

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Title: Genome-wide association study of leukotriene modifier response in asthma
Author: Dahlin, A; Litonjua, A; Irvin, C G; Peters, S P; Lima, J J; Kubo, M; Tamari, M; Tantisira, K G

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Citation: Dahlin, A, A Litonjua, C G Irvin, S P Peters, J J Lima, M Kubo, M Tamari, and K G Tantisira. 2016. “Genome-wide association study of leukotriene modifier response in asthma.” The Pharmacogenomics Journal 16 (2): 151-157. doi:10.1038/tpj.2015.34.
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Abstract: 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.
Published Version: doi:10.1038/tpj.2015.34
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