The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma

Amber Dahlin, Weiliang Qiu, Augusto A. Litonjua, John J. Lima, Mayumi Tamari, Michiaki Kubo, Charles G. Irvin, Stephen P. Peters, Ann C. Wu, Scott T. Weiss, Kelan G. Tantisira

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB 4 production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB 4 production in LCLs following zileuton treatment (i.e., ‘poor’ responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB 4 production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.

Original languageEnglish
Pages (from-to)665-677
Number of pages13
JournalPharmacogenomics Journal
Volume18
Issue number5
DOIs
Publication statusPublished - 01-09-2018

Fingerprint

zileuton
Phosphotransferases
Asthma
Quantitative Trait Loci
Cell Line
Genes
Leukotriene Antagonists
Lung

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Dahlin, Amber ; Qiu, Weiliang ; Litonjua, Augusto A. ; Lima, John J. ; Tamari, Mayumi ; Kubo, Michiaki ; Irvin, Charles G. ; Peters, Stephen P. ; Wu, Ann C. ; Weiss, Scott T. ; Tantisira, Kelan G. / The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 5. pp. 665-677.
@article{152f7125ccf84114bfc81eeda930e948,
title = "The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma",
abstract = "Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB 4 production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB 4 production in LCLs following zileuton treatment (i.e., ‘poor’ responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB 4 production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.",
author = "Amber Dahlin and Weiliang Qiu and Litonjua, {Augusto A.} and Lima, {John J.} and Mayumi Tamari and Michiaki Kubo and Irvin, {Charles G.} and Peters, {Stephen P.} and Wu, {Ann C.} and Weiss, {Scott T.} and Tantisira, {Kelan G.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1038/s41397-017-0006-0",
language = "English",
volume = "18",
pages = "665--677",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "5",

}

Dahlin, A, Qiu, W, Litonjua, AA, Lima, JJ, Tamari, M, Kubo, M, Irvin, CG, Peters, SP, Wu, AC, Weiss, ST & Tantisira, KG 2018, 'The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma', Pharmacogenomics Journal, vol. 18, no. 5, pp. 665-677. https://doi.org/10.1038/s41397-017-0006-0

The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma. / Dahlin, Amber; Qiu, Weiliang; Litonjua, Augusto A.; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Wu, Ann C.; Weiss, Scott T.; Tantisira, Kelan G.

In: Pharmacogenomics Journal, Vol. 18, No. 5, 01.09.2018, p. 665-677.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma

AU - Dahlin, Amber

AU - Qiu, Weiliang

AU - Litonjua, Augusto A.

AU - Lima, John J.

AU - Tamari, Mayumi

AU - Kubo, Michiaki

AU - Irvin, Charles G.

AU - Peters, Stephen P.

AU - Wu, Ann C.

AU - Weiss, Scott T.

AU - Tantisira, Kelan G.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB 4 production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB 4 production in LCLs following zileuton treatment (i.e., ‘poor’ responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB 4 production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.

AB - Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB 4 production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB 4 production in LCLs following zileuton treatment (i.e., ‘poor’ responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB 4 production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.

UR - http://www.scopus.com/inward/record.url?scp=85040069835&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040069835&partnerID=8YFLogxK

U2 - 10.1038/s41397-017-0006-0

DO - 10.1038/s41397-017-0006-0

M3 - Article

C2 - 29298996

AN - SCOPUS:85040069835

VL - 18

SP - 665

EP - 677

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 5

ER -