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 language | English |
|---|---|
| Pages (from-to) | 151-157 |
| Number of pages | 7 |
| Journal | Pharmacogenomics Journal |
| Volume | 16 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 01-04-2016 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Genetics
- Pharmacology
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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 journal › Article
TY - JOUR
T1 - Genome-wide association study of leukotriene modifier response in asthma
AU - Dahlin, A.
AU - Litonjua, A.
AU - Irvin, C. G.
AU - Peters, S. P.
AU - Lima, J. J.
AU - Kubo, Michiaki
AU - Tamari, M.
AU - Tantisira, K. G.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84930325062&partnerID=8YFLogxK
U2 - 10.1038/tpj.2015.34
DO - 10.1038/tpj.2015.34
M3 - Article
C2 - 26031901
AN - SCOPUS:84930325062
VL - 16
SP - 151
EP - 157
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
SN - 1470-269X
IS - 2
ER -