Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension

Raymond L. Benza, Mardi Gomberg-Maitland, Teresa Demarco, Adaani E. Frost, Adam Torbicki, David Langleben, Tomas Pulido, Priscilla Correa-Jaque, Michael J. Passineau, Howard W. Wiener, Mayumi Tamari, Tomomitsu Hirota, Michiaki Kubo, Hemant K. Tiwari

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Singlenucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

Original languageEnglish
Pages (from-to)1345-1354
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume192
Issue number11
DOIs
Publication statusPublished - 01-12-2015

Fingerprint

Endothelin-1
Pulmonary Hypertension
GTP-Binding Protein gamma Subunits
GTP-Binding Protein alpha Subunits
Genes
Endothelin A Receptors
Genome-Wide Association Study
Endothelins
Dyspnea
Single Nucleotide Polymorphism
Blood Vessels
Cohort Studies
Therapeutics
Outcome Assessment (Health Care)
Prospective Studies
Exercise
Lung
Mutation

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Benza, R. L., Gomberg-Maitland, M., Demarco, T., Frost, A. E., Torbicki, A., Langleben, D., ... Tiwari, H. K. (2015). Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 192(11), 1345-1354. https://doi.org/10.1164/rccm.201501-0196OC
Benza, Raymond L. ; Gomberg-Maitland, Mardi ; Demarco, Teresa ; Frost, Adaani E. ; Torbicki, Adam ; Langleben, David ; Pulido, Tomas ; Correa-Jaque, Priscilla ; Passineau, Michael J. ; Wiener, Howard W. ; Tamari, Mayumi ; Hirota, Tomomitsu ; Kubo, Michiaki ; Tiwari, Hemant K. / Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension. In: American Journal of Respiratory and Critical Care Medicine. 2015 ; Vol. 192, No. 11. pp. 1345-1354.
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abstract = "Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Singlenucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.",
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Benza, RL, Gomberg-Maitland, M, Demarco, T, Frost, AE, Torbicki, A, Langleben, D, Pulido, T, Correa-Jaque, P, Passineau, MJ, Wiener, HW, Tamari, M, Hirota, T, Kubo, M & Tiwari, HK 2015, 'Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension', American Journal of Respiratory and Critical Care Medicine, vol. 192, no. 11, pp. 1345-1354. https://doi.org/10.1164/rccm.201501-0196OC

Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension. / Benza, Raymond L.; Gomberg-Maitland, Mardi; Demarco, Teresa; Frost, Adaani E.; Torbicki, Adam; Langleben, David; Pulido, Tomas; Correa-Jaque, Priscilla; Passineau, Michael J.; Wiener, Howard W.; Tamari, Mayumi; Hirota, Tomomitsu; Kubo, Michiaki; Tiwari, Hemant K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 11, 01.12.2015, p. 1345-1354.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endothelin-1 pathway polymorphisms and outcomes in pulmonary arterial hypertension

AU - Benza, Raymond L.

AU - Gomberg-Maitland, Mardi

AU - Demarco, Teresa

AU - Frost, Adaani E.

AU - Torbicki, Adam

AU - Langleben, David

AU - Pulido, Tomas

AU - Correa-Jaque, Priscilla

AU - Passineau, Michael J.

AU - Wiener, Howard W.

AU - Tamari, Mayumi

AU - Hirota, Tomomitsu

AU - Kubo, Michiaki

AU - Tiwari, Hemant K.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Singlenucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

AB - Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. Objectives: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). Methods: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Singlenucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. Measurements and Main Results: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. Conclusions: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

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