Genome-wide association study of leukotriene modifier response in asthma.
Dahlin, A; Litonjua, A; Irvin, C G; Peters, S P; Lima, J J; Kubo, M; Tamari, M; Tantisira, K G
[Article] Pharmacogenomics Journal. 16(2):151-157, April 2016.

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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 x E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second ([DELTA]FEV1) 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 x 10-08); homozygous rs12436663 carriers showed a significant reduction in mean [DELTA]FEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P = 1.25 x 10-07). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.

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