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Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension
- Source :
- JAMA Cardiology. 5:677
- Publication Year :
- 2020
- Publisher :
- American Medical Association (AMA), 2020.
-
Abstract
- 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.To identify novel IPAH susceptibility genes other than BMPR2.This 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants 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.PTGIS rare variants.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.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 of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare 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 without PTGIS variants, 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 .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1GA 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.This study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.
- Subjects :
- Adult
Male
medicine.medical_specialty
Genome-wide association study
030204 cardiovascular system & hematology
Gastroenterology
Young Adult
03 medical and health sciences
0302 clinical medicine
Cytochrome P-450 Enzyme System
Internal medicine
medicine
Humans
Familial Primary Pulmonary Hypertension
Genetic Predisposition to Disease
Pulmonary Wedge Pressure
030212 general & internal medicine
Whole Genome Sequencing
business.industry
Case-control study
Odds ratio
medicine.disease
Pulmonary hypertension
BMPR2
Phenotype
medicine.anatomical_structure
Case-Control Studies
Cohort
Vascular resistance
Female
Vascular Resistance
Cardiology and Cardiovascular Medicine
business
Iloprost
medicine.drug
Subjects
Details
- ISSN :
- 23806583
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- JAMA Cardiology
- Accession number :
- edsair.doi.dedup.....6733b684f2839ce3ae5a6899f42a8fa1