Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension
Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension
复制标题
种系 BMP9 突变导致特发性肺动脉高压。
DOI：
10.1183/13993003.01609-2018
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发表时间：
2019-03-01
影响因子：
24.3
通讯作者：
Jing, Zhi-Cheng
中科院分区：
文献类型：
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作者：
Wang, Xiao-Jian;Lian, Tian-Yu;Jing, Zhi-Cheng
背景特发性肺动脉高压（IPAH）是一种罕见的高遗传性疾病。虽然有几个易感基因与IPAH有关，但大量IPAH病例的遗传病因仍然未知。方法对331例IPAH患者和10 508例对照者进行了两项独立的病例对照研究，并进行了基于外显子组的基因负荷分析。 进行功能评估以分析基因突变对蛋白质生物合成和功能的影响。结果编码人骨形态发生蛋白9（BMP 9）的基因被鉴定为一个新的遗传位点，在发现队列中显示与IPAH的外显子组范围相关（OR 18.8; p=1.9×10−11）。这种关联在独立重复队列中得到了验证（p=1.0×10−5）。总的来说，BMP 9中罕见的编码突变发生在6.7%的病例中，该基因仅次于BMPR 2，组合显著性为2.7×10−19（OR 21.2）。有趣的是，有BMP 9突变的患者的血浆BMP 9水平低于没有突变的患者。功能研究表明，BMP 9突变导致肺动脉内皮细胞BMP 9分泌减少，抗凋亡能力受损。结论BMP 9为IPAH的致病基因。BMP 9是IPAH的一个新的致病基因，仅次于BMPR 2。BMP 9中罕见的有害突变导致BMP 9分泌减少和BMP 9功能受损，占IPAH病例的6.7%。http://ow.ly/h0tS30mXr8j
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