项目名称: 肥厚型心肌病致病基因复合突变剂量效应及其分子机制研究
项目编号: No.81470503
项目类型: 面上项目
立项/批准年度: 2015
项目学科: 医药、卫生
项目作者: 王虎
作者单位: 中国医学科学院阜外医院
项目金额: 73万元
中文摘要: 肥厚型心肌病(HCM)是导致年轻人猝死的最主要原因之一。我们在前期研究中用高通量测序技术对已收集的746例国人HCM患者的26个致病基因分析发现,携带2个以上致病基因突变的患者占比高达17%,且其临床表型比仅携带单个突变的患者显著加重,如发病早、猝死率高、心肌肥厚程度重等,这种基因突变的剂量效应(Dosage-effect)可能是影响前期报道的HCM患者基因型-临床表型关联变异较大的重要原因之一。本课题拟收集HCM患者至1000例(已收集746例)并进行高通量测序,建立较全面的国人HCM患者基因型-临床表型关联,从而初步实现对突变携带者进行危险分层,判断预后,实施临床早期预警和干预。同时利用基因敲入(Knock-In)小鼠模型研究剂量效应的分子机制,这不仅有助于更准确的建立HCM基因型-临床表型的关联,而且可以为治疗病理性心肌重塑提供可能的新靶点和新思路。
中文关键词: 心肌病;肥厚型心肌病;基因突变
英文摘要: Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiac diseases. The disease affects all age groups with marked clinical heterogeneity, ranging from a normal lifespan without symptoms to poor outcomes such as sudden cardiac death (SCD), advanced heart failure or stroke. Identification of patients with a poor prognosis has a great impact on improving clinical outcomes, including prevention of SCD. Several variables have been generally accepted as risk factors for SCD, including family history of SCD, unexplained syncope, non-sustained ventricular tachycardia, severe cardiac hypertrophy and abnormal blood pressure response to exercise. However, these factors have a low positive predictive value and are unable to predict the clinical outcomes of HCM-related heart failure and stroke. In our previous study, a total of 746 unrelated HCM patients were prospectively recruited. The 26 disease-causing genes of HCM were comprehensively screened by using multiplexing targeted sequencing. All coding exons and their adjacent 5 bp intronic sequences were enriched using a custom designed probe library and sequenced. Multiple mutations were identified in 17% of the study patients. The risk for cardiovascular death in patients with multiple mutations was higher than those without rare variant or those with single rare variant. Multivariate analysis revealed multiple rare variants were an independent risk factor for cardiovascular death (HR 3.74, 95% CI 1.84 to 7.58, P=0.0003), as well as sudden cardiac death (HR 3.57, 95% CI 1.23-10.35, P=0.019) and heart failure-related death (HR 4.62, 95% CI 1.67-12.76, P=0.003). These patients exhibit earlier and more severe clinical manifestations, suggesting the presence of a dosage effect of mutations on the severity of the phenotype. The presence of multiple mutations in related genes is an independent risk factor for poor outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients. In this project, we aim to investigate the molecular mechanisms of dosage-effect of multiple mutations in disease-causing genes on clinical manifestation of HCM patients using konck-in mouse models.
英文关键词: Cardiomyopathy;Hypertropic Cardiomyopathy;Mutation