RT Journal Article
SR Electronic
T1 Germline <em>BMP9</em> mutation causes idiopathic pulmonary arterial hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1801609
DO 10.1183/13993003.01609-2018
VO 53
IS 3
A1 Xiao-Jian Wang
A1 Tian-Yu Lian
A1 Xin Jiang
A1 Shao-Fei Liu
A1 Su-Qi Li
A1 Rong Jiang
A1 Wen-Hui Wu
A1 Jue Ye
A1 Chun-Yan Cheng
A1 Yao Du
A1 Xi-Qi Xu
A1 Yan Wu
A1 Fu-Hua Peng
A1 Kai Sun
A1 Yi-Min Mao
A1 Huan Yu
A1 Chen Liang
A1 John Y-J. Shyy
A1 Shu-Yang Zhang
A1 Xue Zhang
A1 Zhi-Cheng Jing
YR 2019
UL http://erj.ersjournals.com/content/53/3/1801609.abstract
AB 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.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