Lyu Zi-Chao, Wang Lan, Lin Jian-Hui, Li Su-Qi, Wu Dan-Chen, Lian Tian-Yu, Liu Shao-Fei, Ye Jue, Jiang Xin, Wang Xiao-Jian, Jing Zhi-Cheng
Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Int J Cardiol. 2020 Nov 1;318:138-143. doi: 10.1016/j.ijcard.2020.06.068. Epub 2020 Jul 4.
Mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2) are the most common genetic risk factors underlying pulmonary arterial hypertension (PAH). However, the features of PAH-related BMPR2 rare variants remain unclear. We propose that the discrepancy of BMPR2 rare variants landscape between patients with PAH and reference population would be important to address the genetic background of PAH-related variants.
We genotyped BMPR2 rare variants in 670 Chinese patients with pulmonary arterial hypertension. The BMPR2 rare variants were screened in 10,508 reference people from two exome databases.
The prevalence of rare BMPR2 variants in patients with PAH was significantly higher compared to the reference population (21.5%, 144/670 vs 0.87%, 91/10508, p = 1.3 × 10). In patients with PAH, 49% of identified BMPR2 rare variants were loss-of-function or splicing. These BMPR2 rare variants were only observed in 1% of the reference population (p = 9.0 × 10). Arg491, which is absent in the reference population, represented as hot-spot site (14.6%, 21/144) in PAH patients. BMPR2 missense mutations in PAH patients were more likely distributed in extracellular ligand-binding domain (ECD, 29.7% vs 11.1%, p < 0.001). Compared with Non-PAH-related variations, PAH-related missense variants tend to alter the amino acid electric status (51.4% vs 23.3%, p < 0.001).
BMPR2 variants located in extracellular ligand-binding domain or altered the amino acid electric status are more pathogenic.
编码骨形态发生蛋白受体2型（BMPR2）的基因突变是肺动脉高压（PAH）最常见的遗传风险因素。然而，PAH相关BMPR2罕见变异的特征仍不清楚。我们认为，PAH患者与参考人群之间BMPR2罕见变异情况的差异对于阐明PAH相关变异的遗传背景很重要。
我们对670例中国肺动脉高压患者的BMPR2罕见变异进行了基因分型。在来自两个外显子数据库的10508名参考人群中筛选BMPR2罕见变异。
与参考人群相比，PAH患者中罕见BMPR2变异的患病率显著更高（21.5%，144/670 vs 0.87%，91/10508，p = 1.3×10）。在PAH患者中，49%已鉴定的BMPR2罕见变异为功能丧失或剪接变异。这些BMPR2罕见变异仅在1%的参考人群中观察到（p = 9.0×10）。参考人群中不存在的Arg491在PAH患者中是热点位点（14.6%，21/144）。PAH患者中的BMPR2错义突变更可能分布在细胞外配体结合域（ECD，29.7%对11.1%，p < 0.001）。与非PAH相关变异相比，PAH相关错义变异倾向于改变氨基酸电状态（51.4%对23.3%，p < 0.001）。
位于细胞外配体结合域或改变氨基酸电状态的BMPR2变异更具致病性。
