Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension | Cardiology | JN Learning | AMA Ed Hub [Skip to Content]
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Cardiology

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

Educational Objective
To review the role of the prostacyclin pathway and the prostaglandin I2 synthase gene in pulmonary arterial hypertension.
1 Credit CME
JAMA Cardiology
June 1, 2020
Original Investigation
Xiao-Jian Wang, PhD1;
Xi-Qi Xu, MD1,2;
Kai Sun, PhD1,2;
Ke-Qiang Liu, PhD3;
Su-Qi Li, MS1;
Xin Jiang, MD1,2;
Qin-Hua Zhao, MD4;
Lan Wang, MD4;
Fu-Hua Peng, MD1;
Jue Ye, BS1;
Yan Wu, MD1;
Rui Jiang, PhD5;
Jin Zhang, BS6;
Wei Huang, MD7;
Wen-Bin Wei, MD8;
Yi Yan, MD1;
Jing-Hui Li, MD1;
Qian-Qian Liu, MD1;
Sheng Li, PhD9;
Yong Wang, MD10;
Shu-Yang Zhang, MD2;
Xue Zhang, PhD3;
Zhi-Cheng Jing, MD2
Author Affiliations
  • 1State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  • 2Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
  • 3McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Peking Union Medical College, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
  • 4Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
  • 5Ministry of Education (MOE) Key Laboratory of Bioinformatics, Bioinformatics Division, Beijing National Research Center for Information Science and Technology, Department of Automation, Tsinghua University, Beijing, China
  • 6Cardiovascular Research Center, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China
  • 7Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
  • 8Cardiovascular Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
  • 9Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China
  • 10Department of Respiratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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Key Points

Question  What is the novel susceptibility gene for idiopathic pulmonary arterial hypertension?

Findings  In this 2-stage genetic association study of 230 patients with idiopathic pulmonary arterial hypertension, heterozygous rare PTGIS variants were first found significantly overrepresented in 6.1%, conferring 7.8 higher odds of pulmonary arterial hypertension. In addition, patients carrying rare PTGIS variants were more responsive to iloprost stimulation than those without such variants.

Meaning  The rare variants of the PTGIS gene appear to contribute higher susceptibility to idiopathic pulmonary arterial hypertension, and screening of PTGIS variants may help improve personalized treatment of these patients.

Abstract

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.

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Cardiology Genetics and Genomics Pulmonary Medicine
Article Information

Accepted for Publication: February 12, 2020.

Published Online: April 1, 2020. doi:10.1001/jamacardio.2020.0479

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Wang X-J et al. JAMA Cardiology.

Corresponding Authors: Zhi-Cheng Jing, MD, Key Laboratory of Pulmonary Vascular Medicine, Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing 100730, China (jingzhicheng@vip.163.com); Xue Zhang, PhD, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Peking Union Medical College, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, No. 9 Dongdansantiao, Dongcheng District, Beijing 100730, China (xuezhang@pumc.edu.cn).

Author Contributions: Drs X-J Wang, Xu, and Sun served as co–first authors and contributed equally to this article. Dr Jing had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: X-J Wang, Sun, S-Y Zhang, X Zhang, Jing.

Acquisition, analysis, or interpretation of data: X-J Wang, Xu, Sun, K-Q Liu, S-Q Li, X Jiang, Zhao, L Wang, Peng, Ye, Wu, R Jiang, J Zhang, Huang, Wei, Yan, J-H Li, Q-Q Liu, S Li, Y Wang.

Drafting of the manuscript: X-J Wang, Xu, Sun, R Jiang, J Zhang, S-Y Zhang, Jing.

Critical revision of the manuscript for important intellectual content: X-J Wang, Xu, Sun, K-Q Liu, S-Q Li, X Jiang, Zhao, L Wang, Peng, Ye, Wu, Huang, Wei, Yan, J-H Li, Q-Q Liu, S Li, Y Wang, S-Y Zhang, X Zhang, Jing.

Statistical analysis: X-J Wang, Xu, Sun, R Jiang.

Obtained funding: X-J Wang, S-Y Zhang, X Zhang, Jing.

Administrative, technical, or material support: Xu, K-Q Liu, S-Q Li, X Jiang, Zhao, L Wang, Peng, Ye, J Zhang, Huang, Wei, Yan, J-H Li, Q-Q Liu, S Li, Y Wang, S-Y Zhang, X Zhang, Jing.

Supervision: S-Y Zhang, Jing.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants 7181009 and 7172180 from the Beijing Natural Science Foundation; grant 2016YFC0901502 from the National Key Research and Development Program of China; grants 81630003, 81670052, and 81870050 from the National Natural Science Foundation of China; grant 2018ZX09711001-003-012 from the Drug Innovation Major Project; grants 2016-I2M-1-002, 2016-I2M-4-003, 2017-I2M-3-003, 2017-I2M-1-004, and 2017-I2M-2-001 from the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; grant 2017PT32016 from the CAMS Fund for Key Laboratory of Pulmonary Vascular Medicine; grant 2018RC310007 from the CAMS Fund for Young Talents of Medical Science; and grant SZSM201502001 from the Sanming Project of Medicine in Shenzhen (Dr Jing’s group for Precise Medicine Research in Thrombosis and Vascular Disease).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patients and families for their support and contribution to this study. Meng-Meng Wu, PhD, Bioinformatics Division, Department of Automation, Tsinghua University, Beijing, China, processed data from whole-genome sequencing. Huan Yu, BS, Novogene Co, Ltd, assisted in bioinformatics analyses. John Y-J. Shyy, PhD, Department of Medicine, University of California, San Diego, provided critical review of the manuscript. Duo-Lao Wang, PhD, Department of Clinical Sciences, Liverpool School of Tropical Medicine (LSTM), Liverpool, UK, provided statistical assistance. None of these contributors were compensated for this work.

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