RGD Reference Report - Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension. - Rat Genome Database

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

Authors: Wang, Xiao-Jian  Xu, Xi-Qi  Sun, Kai  Liu, Ke-Qiang  Li, Su-Qi  Jiang, Xin  Zhao, Qin-Hua  Wang, Lan  Peng, Fu-Hua  Ye, Jue  Wu, Yan  Jiang, Rui  Zhang, Jin  Huang, Wei  Wei, Wen-Bin  Yan, Yi  Li, Jing-Hui  Liu, Qian-Qian  Li, Sheng  Wang, Yong  Zhang, Shu-Yang  Zhang, Xue  Jing, Zhi-Cheng 
Citation: Wang XJ, etal., JAMA Cardiol. 2020 Jun 1;5(6):677-684. doi: 10.1001/jamacardio.2020.0479.
RGD ID: 401901150
Pubmed: PMID:32236489   (View Abstract at PubMed)
PMCID: PMC7113838   (View Article at PubMed Central)
DOI: DOI:10.1001/jamacardio.2020.0479   (Journal Full-text)

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 than BMPR2.
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 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.
EXPOSURES: PTGIS rare 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 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 + 1G>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 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanprimary pulmonary hypertension  IAGP DNA:SNP more ...RGD 
PtgisRatprimary pulmonary hypertension  ISOPTGIS (Homo sapiens)DNA:SNP more ...RGD 
PtgisMouseprimary pulmonary hypertension  ISOPTGIS (Homo sapiens)DNA:SNP more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanPulmonary arterial hypertension  IAGP DNA:SNP more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ptgis  (prostaglandin I2 synthase)

Genes (Mus musculus)
Ptgis  (prostaglandin I2 (prostacyclin) synthase)

Genes (Homo sapiens)
PTGIS  (prostaglandin I2 synthase)

Additional Information