Shen Cheng, Xu Lei, Sun Xiaoning, Sun Aijun, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, China.
Ann Transl Med. 2022 Feb;10(3):129. doi: 10.21037/atm-21-6774.
Multiple genes have been associated with familial dilated cardiomyopathy (DCM). However, the role of genetic factors in sporadic DCM (SDCM) remains unclear. Therefore, we studied the genetic variations in Chinese patients with SDCM.
Sixty-six unrelated Chinese patients (mean age 49.1±17.0 years; 71% male) diagnosed with SDCM were enrolled. The clinical history and genomic DNA of the cohort were collected and examined. The exons of 24 genes closely associated with familial DCM (, and ) were sequenced using targeted next-generation sequencing method. All called nonsynonymous variants and their occurrence frequencies were compared against population data from public databases. And the nonsynonymous variants were also evaluated for pathogenicity by PolyPhen 2 (PP2) and Sorts Intolerant From Tolerant (SIFT) algorithms.
Eighty-five nonsynonymous variants were detected in 17 genes. The variants and their occurrence frequencies in the patients were compared against population data from the 1000 Genomes and NHLBI (National Heart, Lung, and Blood Institute) Go Exome Sequencing Project. Forty-nine nonsynonymous variants had occurrence frequencies that were significantly higher in the study patients than in the general population, indicating that they have the potential to increase the risk of DCM. The risk variants were distributed in 40 (61%) patients, among whom 25 carried a single variant, while the remaining patients carried multiple (2 to 4) variants. Risk variants occurred more frequently in (14% of the patients), (14%), (12%), (9%), and (8%), as verified by Poisson distribution analysis, which were considered "the five risky genes".
We found that genetic variants with potential risk for DCM were commonly present in SDCM patients, indicating that genetic factors contribute to the pathogenesis, and (probably) the onset, of DCM in these patients.
多个基因已被证实与家族性扩张型心肌病（DCM）相关。然而，遗传因素在散发性扩张型心肌病（SDCM）中的作用仍不明确。因此，我们对中国SDCM患者的基因变异情况展开了研究。
纳入66例确诊为SDCM的无血缘关系的中国患者（平均年龄49.1±17.0岁；71%为男性）。收集并检查该队列的临床病史和基因组DNA。采用靶向二代测序方法对24个与家族性DCM密切相关的基因（ 、 及 ）的外显子进行测序。将所有检测到的非同义变异及其出现频率与公共数据库中的人群数据进行比较。同时，利用PolyPhen 2（PP2）和从耐受中筛选不耐受（SIFT）算法对非同义变异的致病性进行评估。
在17个基因中检测到85个非同义变异。将患者中的变异及其出现频率与来自千人基因组计划和美国国立心肺血液研究所（NHLBI）外显子组测序计划的人群数据进行比较。49个非同义变异在研究患者中的出现频率显著高于一般人群，表明它们有可能增加患DCM的风险。这些风险变异分布于40例（61%）患者中，其中25例携带单个变异，其余患者携带多个（2至4个）变异。经泊松分布分析验证，风险变异在 （14%的患者）、 （14%）、 （12%）、 （9%）和 （8%）基因中出现频率更高，这些基因被视为“五个风险基因”。
我们发现，具有DCM潜在风险的基因变异在SDCM患者中普遍存在，这表明遗传因素在这些患者DCM的发病机制以及（可能）发病过程中发挥了作用。
