Genome-wide association study of leukotriene modifier response in asthma

A. Dahlin, A. Litonjua, C. G. Irvin, S. P. Peters, J. J. Lima, M. Kubo, M. Tamari, K. G. Tantisira

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31 Citations (Scopus)


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 (ΔFEV 1) 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 ΔFEV 1 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.

Original languageEnglish
Pages (from-to)151-157
Number of pages7
JournalPharmacogenomics Journal
Issue number2
Publication statusPublished - 01-04-2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology


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