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 etiology remains unknown for a large number of IPAH cases.
Methods We conducted an exome-wide gene-based burden analysis on 2 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 the human bone morphogenetic protein 9 (BMP9) was identified as a novel genetic locus displaying exome-wide association with IPAH in the discovery cohort (odds ratios, 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 gene occurred in 6.7% of cases, ranking this gene second to BMPR2, comprising a combined significance of 2.7×10−19 (odds ratio, 21.2). Intriguingly, the patients with BMP9 mutations had lower plasma level 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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Cheng has nothing to disclose.
Conflict of interest: Dr. Du has nothing to disclose.
Conflict of interest: Dr. Jiang has nothing to disclose.
Conflict of interest: Dr. Jiang has nothing to disclose.
Conflict of interest: Dr. Jing has nothing to disclose.
Conflict of interest: Dr. Liang has nothing to disclose.
Conflict of interest: Dr. Lian has nothing to disclose.
Conflict of interest: Dr. Li has nothing to disclose.
Conflict of interest: Dr. Liu has nothing to disclose.
Conflict of interest: Dr. Mao has nothing to disclose.
Conflict of interest: Dr. Peng has nothing to disclose.
Conflict of interest: Dr. Shyy has nothing to disclose.
Conflict of interest: Dr. Sun has nothing to disclose.
Conflict of interest: Dr. Wang has nothing to disclose.
Conflict of interest: Dr. W-H. Wu has nothing to disclose.
Conflict of interest: Dr. Y. Wu has nothing to disclose.
Conflict of interest: Dr. Xu has nothing to disclose.
Conflict of interest: Jue Ye has nothing to disclose.
Conflict of interest: Dr. Yu has nothing to disclose.
Conflict of interest: Dr. Zhang has nothing to disclose.
Conflict of interest: Dr. Zhang has nothing to disclose.
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