Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension.

Importance Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation. Objective To identify novel IPAH susceptibility genes other thanBMPR2. Design, Setting, and Participants This 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had noBMPR2variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018. Exposures PTGISrare variants. Main Outcomes and Measures Whole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes. Results Among 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association ofPTGISrare variants with IPAH was confirmed in the replication cohort. In the combined data set,PTGISrare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8;P = 5 × 10−6, logistic regression). Compared with patients withoutPTGISvariants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, −21.7%; 95% CI, −31.4% to −12.0%;P  A variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells. Conclusions and Relevance This study identified 3 rare loss-of-function variants in thePTGISgene from 2 independent cohorts with IPAH. The genetic variants ofPTGISpredispose pulmonary vascular responses to the iloprost stimulation. These findings suggest thatPTGISvariants may be involved in the pathogenesis of IPAH.