The features of rare pathogenic BMPR2 variants in pulmonary arterial hypertension: Comparison between patients and reference population
The features of rare pathogenic BMPR2 variants in pulmonary arterial hypertension: Comparison between patients and reference population
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肺动脉高压罕见致病性BMPR2变异的特征：患者与参考人群的比较
DOI：
10.1016/j.ijcard.2020.06.068
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发表时间：
2020-11-01
影响因子：
3.5
通讯作者：
Jing, Zhi-Cheng
中科院分区：
文献类型：
--
作者：
Lyu, Zi-Chao;Wang, Lan;Jing, Zhi-Cheng
背景资料：编码骨形态发生蛋白受体2（BMPR 2）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相关的BMPR 2罕见变体的特征仍不清楚。我们建议PAH患者和参考人群之间BMPR 2罕见变异景观的差异对于解决PAH相关variants.Methods的遗传背景非常重要：我们对670例中国肺动脉高压患者进行BMPR 2罕见变异基因分型。结果：PAH患者罕见BMPR 2变异的患病率显著高于对照人群（21.5%，144/670 vs 0.87%，91/10508，p = 1.3 x 10（-118））。在PAH患者中，49%的BMPR 2罕见变异是功能丧失或剪接。仅在1%的参考人群中观察到这些BMPR 2罕见变异体（p = 9.0 x 10（-12））。Arg 491在PAH患者中为热点位点（14.6%，21/144），在参考人群中缺失。PAH患者中的BMPR 2错义突变更可能分布在细胞外配体结合结构域（ECD，29.7%对11.1%，p < 0.001）。与非PAH相关突变相比，PAH相关的错义突变更易改变氨基酸电状态（51.4%vs23.3%，p < 0.001）。结论：位于胞外配体结合区的BMPR 2突变或改变氨基酸电状态的BMPR 2突变具有更强的致病性。(C)2020爱思唯尔B. V.保留所有权利。
Background: 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 disaepancy of BMPR2 rare variants landscape between patients with PAH and reference population would be important to address the genetic background of PAH-related variants.Methods: We genotyped BMPR2 rare variants in 670 Chinese patients with pulmonaly arterial hypertension. The BMPR2 rare variants were screened in 10,508 reference people from two exome databases.Results: 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 x 10(-118)). 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 x 10(-12)). Arg491, which is absent in the reference population, represented as hotspot 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 1 1.1%, 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).Conclusions: BMPR2 variants located in extracellular Iigand-binding domain or altered the amino acid electric status are more pathogenic. (C) 2020 Elsevier B.V. All rights reserved.