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

doi:10.1038/tpj.2015.34

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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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	https://doi.org/10.1038/tpj.2015.34
Publication status	Published - 01-04-2016

All Science Journal Classification (ASJC) codes

Molecular Medicine
Genetics
Pharmacology

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title = "Genome-wide association study of leukotriene modifier response in asthma",

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.",

author = "A. Dahlin and A. Litonjua and Irvin, {C. G.} and Peters, {S. P.} and Lima, {J. J.} and M. Kubo and M. Tamari and Tantisira, {K. G.}",

note = "Funding Information: We thank collaborators and research staff at the many study sites, as well as the study participants, for their generous contributions. We also thank Dr Jeffrey Drazen for his significant assistance with this study. This study is supported by the National Institutes of Health - R01 HL092197, U01 HL65899 and R01 NR013391. This study is also supported by the NIH Pharmacogenomics Research Network (PGRN)—RIKEN Center for Genomic Medicine (CGM) Global Alliance and by funding from the BioBank Japan project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. AD is supported by NHLBI K12 HL120004. We acknowledge the American Lung Association (ALA) and the ALA''s Asthma Clinical Research Centers investigators and research teams for the use of LOCCS and LODO data, with additional funding from HL071394 and HL074755 from the NHLBI, and Nemours Children''s'' Clinic. GlaxoSmithKline supported the conduct of the LOCCS trial by an unrestricted grant to the ALA.",

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doi = "10.1038/tpj.2015.34",

language = "English",

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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, M.

AU - Tamari, M.

AU - Tantisira, K. G.

N1 - Funding Information: We thank collaborators and research staff at the many study sites, as well as the study participants, for their generous contributions. We also thank Dr Jeffrey Drazen for his significant assistance with this study. This study is supported by the National Institutes of Health - R01 HL092197, U01 HL65899 and R01 NR013391. This study is also supported by the NIH Pharmacogenomics Research Network (PGRN)—RIKEN Center for Genomic Medicine (CGM) Global Alliance and by funding from the BioBank Japan project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. AD is supported by NHLBI K12 HL120004. We acknowledge the American Lung Association (ALA) and the ALA''s Asthma Clinical Research Centers investigators and research teams for the use of LOCCS and LODO data, with additional funding from HL071394 and HL074755 from the NHLBI, and Nemours Children''s'' Clinic. GlaxoSmithKline supported the conduct of the LOCCS trial by an unrestricted grant to the ALA.

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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.

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