Genome-wide association study of leukotriene modifier response in asthma

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 (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
Volume16
Issue number2
DOIs
Publication statusPublished - 01-04-2016

Fingerprint

zileuton
Leukotrienes
Genome-Wide Association Study
montelukast
Asthma
Forced Expiratory Volume
Therapeutics
Pharmacogenetics
Genes
Single Nucleotide Polymorphism
Placebos
Genome
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Dahlin, A., Litonjua, A., Irvin, C. G., Peters, S. P., Lima, J. J., Kubo, 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
Dahlin, A. ; Litonjua, A. ; Irvin, C. G. ; Peters, S. P. ; Lima, J. J. ; Kubo, Michiaki ; Tamari, M. ; Tantisira, K. G. / Genome-wide association study of leukotriene modifier response in asthma. In: Pharmacogenomics Journal. 2016 ; Vol. 16, No. 2. pp. 151-157.
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Dahlin, A, Litonjua, A, Irvin, CG, Peters, SP, Lima, JJ, Kubo, M, Tamari, M & Tantisira, KG 2016, 'Genome-wide association study of leukotriene modifier response in asthma', Pharmacogenomics Journal, vol. 16, no. 2, pp. 151-157. https://doi.org/10.1038/tpj.2015.34

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

In: Pharmacogenomics Journal, Vol. 16, No. 2, 01.04.2016, p. 151-157.

Research output: Contribution to journalArticle

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