Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension

作者：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

来源：American Journal of Respiratory and Critical Care Medicine, 2015, 192(11): 1345-1354.

DOI：10.1164/rccm.201501-0196OC

• pulmonary arterial hypertension
• endothelin receptor antagonists
• pharmacogenetics
• polymorphisms

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. Single-nucleotide 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.

• 出版日期2015-12-1