Abstract
Background Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with high heritability. Although several predisposing genes have been linked to IPAH, the genetic aetiology remains unknown for a large number of IPAH cases.
Methods We conducted an exome-wide gene-based burden analysis on two independent case–control studies, including a total of 331 IPAH cases and 10 508 controls. Functional assessments were conducted to analyse the effects of genetic mutations on protein biosynthesis and function.
Results The gene encoding human bone morphogenetic protein 9 (BMP9) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (OR 18.8; p=1.9×10−11). This association was authenticated in the independent replication cohort (p=1.0×10−5). Collectively, the rare coding mutations in BMP9 occurred in 6.7% of cases, ranking this gene second to BMPR2, comprising a combined significance of 2.7×10−19 (OR 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma levels of BMP9 than those without. Functional studies showed that the BMP9 mutations led to reduced BMP9 secretion and impaired anti-apoptosis ability in pulmonary arterial endothelial cells.
Conclusion We identify BMP9 as an IPAH culprit gene.
Abstract
BMP9 is a new culprit gene for IPAH ranking second to BMPR2. The rare deleterious mutations in BMP9, which lead to the reduction in BMP9 secretion and impairment in BMP9 function, account for 6.7% of IPAH cases. http://ow.ly/h0tS30mXr8j
Footnotes
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Conflict of interest: X-J. Wang has nothing to disclose.
Conflict of interest: T-Y. Lian has nothing to disclose.
Conflict of interest: X. Jiang has nothing to disclose.
Conflict of interest: S-F. Liu has nothing to disclose.
Conflict of interest: S-Q. Li has nothing to disclose.
Conflict of interest: R. Jiang has nothing to disclose.
Conflict of interest: W-H. Wu has nothing to disclose.
Conflict of interest: J. Ye has nothing to disclose.
Conflict of interest: C-Y. Cheng has nothing to disclose.
Conflict of interest: Y. Du has nothing to disclose.
Conflict of interest: X-Q. Xu has nothing to disclose.
Conflict of interest: Y. Wu has nothing to disclose.
Conflict of interest: F-H. Peng has nothing to disclose.
Conflict of interest: K. Sun has nothing to disclose.
Conflict of interest: Y-M. Mao has nothing to disclose.
Conflict of interest: H. Yu has nothing to disclose.
Conflict of interest: C. Liang has nothing to disclose.
Conflict of interest: J.Y-J. Shyy has nothing to disclose.
Conflict of interest: S-Y. Zhang has nothing to disclose.
Conflict of interest: X. Zhang has nothing to disclose.
Conflict of interest: Z-C. Jing has nothing to disclose.
Support statement: The work was supported by grants from Beijing Natural Science Foundation (7181009, 7172180), National Key Research and Development Program of China (2016YFC0901502), National Natural Science Foundation of China (81320108005, 81630003, 81670052), National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), and Director Fund from State Key Laboratory of Cardiovascular Disease (2017ZR-03, 2018ZR-02). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received August 24, 2018.
- Accepted November 29, 2018.
- Copyright ©ERS 2019
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