Xiao-Jian Wang1,2, Tian-Yu Lian1,2, Xin Jiang1, Shao-Fei Liu1, Su-Qi Li1, Rong Jiang3, Wen-Hui Wu3, Jue Ye1, Chun-Yan Cheng1, Yao Du1, Xi-Qi Xu1, Yan Wu1, Fu-Hua Peng1, Kai Sun1, Yi-Min Mao4, Huan Yu5, Chen Liang5, John Y-J Shyy6, Shu-Yang Zhang7, Xue Zhang8, Zhi-Cheng Jing1. 1. Key Laboratory of Pulmonary Vascular Medicine and FuWai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2. These two authors contributed equally to this work. 3. Dept of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. 4. Dept of Respiratory Medicine, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China. 5. Novogene Co., Ltd, Beijing, China. 6. Dept of Medicine, University of California San Diego, La Jolla, CA, USA. 7. Dept of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China. 8. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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.
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 humanbone 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.
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