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

研究成果: Article

18 引用 (Scopus)

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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 × 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.

元の言語English
ページ(範囲)151-157
ページ数7
ジャーナルPharmacogenomics Journal
16
発行部数2
DOI
出版物ステータスPublished - 01-04-2016

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

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