PDF(Pubmed)
Abstract：
Background: Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of primary dilated cardiomyopathy (DCM). Likewise, ischemic myocardial injury is a major cause of secondary cardiac remodeling, which, in a subset, is severe and resembles DCM. The latter is referred to as ischemic dilated cardiomyopathy (IDCM). We postulated the presence of pathogenic and likely pathogenic variants (PVs and LPVs, respectively) in genes known to cause primary DCM might predispose the heart to severe cardiac dilatation and dysfunction post myocardial ischemic injury, i.e., IDCM. Methods: We performed whole-exome sequencing in 1,041 patients with primary DCM, 215 patients with IDCM, and 414 healthy controls. Indices of cardiac size and function were similar between those with primary and ischemic DCM. PVs and LPVs, including the truncating variants in 36 genes known to cause primary DCM were identified and compared among the three groups. Results: Pathogenic variants and LPVs were detected in 266 individuals, comprised of 215/1,041 (20.7%) patients with DCM, 27/215 (12.6%) patients with IDCM, and 24/414 (5.8%) control individuals. PVs and LPVs in the TTN gene were the most common and detected in 130/1,041 (12.5%) of patients with DCM, 15/215 (7.0%) of cases with IDCM, and 10/414 (2.4%) control individuals. Of 135 TTNtv, 118 involved exons that were >90% spliced in. These variants were found in 120/1,041 (11.5%) of DCM patients, 6/215 (2.8%) of IDCM cases, and only in 1/414 (0.2%) of the control population (p < 0.001 among the three groups). Conclusions: Pathogenic variants and LPVs in genes known to cause primary DCM are enriched in patients with IDCM, suggesting that such variants function as susceptibility alleles for cardiac dilatation and dysfunction in post myocardial ischemic injury. Thus, IDCM shares a partial genetic etiology with the primary DCM.
摘要：
背景：肌节和细胞骨架蛋白编码基因的突变是原发性扩张型心肌病（DCM）的主要原因。同样，缺血性心肌损伤是继发性心脏重构的主要原因,which,在一个子集中，是严重的，类似于DCM。后者被称为缺血性扩张型心肌病(IDCM)。我们假设存在致病性和可能的致病性变异(PV和LPV，分别）在已知引起原发性DCM的基因中，可能使心脏在心肌缺血损伤后容易发生严重的心脏扩张和功能障碍，即，IDCM。方法：我们对1,041例原发性DCM患者进行了全外显子组测序，215名IDCM患者，和414个健康对照。原发性和缺血性DCM患者的心脏大小和功能指标相似。PV和LPV,包括已知导致原发性DCM的36个基因中的截短变体在内,我们在三组中进行了鉴定和比较.结果：在266例个体中检测到致病性变异和LPV，包括215/1,041（20.7%）DCM患者，27/215（12.6%）IDCM患者，和24/414（5.8％）对照组。在130/1,041(12.5%)的DCM患者中,TTN基因中的PVs和LPVs最为常见,15/215（7.0%）的IDCM病例，和10/414（2.4％）对照组。在135个电视中，118涉及>90%剪接的外显子。这些变异在120/1,041（11.5％）的DCM患者中发现，6/215（2.8%）IDCM病例，仅占对照组的1/414（0.2％）（三组中p<0.001）。结论：已知导致原发性DCM的基因中的致病变异和LPV在IDCM患者中富集，提示这些变异体在心肌缺血后损伤中作为心脏扩张和功能障碍的易感等位基因。因此，IDCM与原发性DCM具有部分遗传病因。
