利用全基因外显子组测序技术搜寻自发性颈动脉夹层发生发展相关易感基因及验证研究

Spontaneous carotid artery dissection(sCAD), which is a multifactorial complex disease with tremendous social and economic burdens, is one of the leading causes of ischemic stroke in adult patients younger than 50 years of age. To date, the pathogenesis of sCAD has been poorly understood. However, more and more evidence showed that the genetic risk factors may play an important role in the occurrence and development of sCAD. Currently, a large multicenter study of sCAD is being performed in the European populations (CADISP-genetics) in order to identify the causative genetic variants, but no similar study has been reported in China. In the preliminary study, our research team analyzed the candidate genes of sCAD in our sCAD patients, a new insertion mutation of the TGFBR1 gene has been detected in two different sporadic sCAD patients, suggesting that the TGFBR1 gene variation may contribute to the genetic susceptibility to sCAD in Han Chinese. The preliminary findings initially confirmed our previous hypotheses. Next we plan to take a combined research strategy of nuclear family with typical sporadic cases and to further search for the genetic susceptibility genes for sCAD in Chinese Han population by whole-exome sequencing, then validation study will be performed to identify the candidate susceptibility genes in a large sporadic sCAD cohort. We believe that our results will have positive effects on the early diagnosis, personalized treatment and health economic policy of sCAD in our country.

自发性颈动脉夹层是一种多因素复杂疾病，是50岁以下中青年发生缺血性卒中的主要原因之一，社会负担和经济负担巨大，至今对其发病机制一直知之甚少。越来越多的研究证据表明，遗传因素在自发性颈动脉夹层的发生发展过程中可能扮演重要角色。目前，欧洲正在进行一项多国共同参与的大型、多中心自发性颈动脉夹层分子遗传学研究（CADISP研究），但国内尚无类似研究的报道。本课题组前期采用候选基因关联研究的方法，首次在2例散发颈动脉夹层患者中检测到了TGFBR1基因的一个插入突变，提示TGFBR1基因变异与汉族自发性颈动脉夹层的易感性相关，初步证实了我们的研究假设。下一步我们将采用核心家系结合典型散发病例的研究策略，利用新一代全基因外显子组测序技术，进一步搜寻与汉族人群自发性颈动脉夹层发病相关的易感基因，并在大样本散发病例中进一步验证，为我国自发性颈动脉夹层患者的早期诊断、个性化治疗及卫生经济政策制定提供参考依据

现有研究结果显示，遗传因素在自发性颈动脉夹层的发生发展过程中发挥重要作用，但我国汉族人群自发性颈动脉夹层患者发病的遗传学背景目前尚不清楚。本研究共纳入300余例中国汉族自发性颈动脉夹层的患者，通过分析总结其临床特征及影像学特点，并采用全基因外显子组测序技术、生物信息学分析和基因芯片大样本量验证测序技术筛选和验证可能与我国汉族自发性颈动脉夹层发病相关的易感基因，揭示我国汉族人群自发性颈动脉夹层发病的遗传学基础。研究结果显示，我国汉族人群自发性颈动脉夹层患者的常见发病年龄是25-55岁，发病高峰年龄是40-50岁，男女发病比例约为1.2:1，最常见的发生部位是颈动脉窦顶部-岩骨段之间。多数患者的影像学表现为“波纹征”样改变伴管腔不同程度的狭窄或者闭塞，少数患者可能表现为典型的“双腔征”或夹层动脉瘤样的改变。自发性颈动脉夹层患者的主要临床表现包括颈部疼痛或不适感、同侧Horner征、TIA发作、脑梗死等，约85%的患者血管形态异常会在发病后的第1个月内完全修复，临床总体预后良好。遗传病因学研究结果显示，MTHFR和TGFBR2基因变异与我国汉族自发性颈动脉夹层患者的发病密切相关，另外尚有GOLGA6L2、ANKRD36C、MUC5AC、ZNF806、MUC3A、SRGAP2B等241个候选易感基因也可能与我国汉族自发性颈动脉夹层患者的发病存在相关性。目前，我们正在进行大样本量的验证测序研究，有望在未来的3个月内完成全部研究，确定最终的易感基因。本项目的研究结果，将为我国汉族自发性颈动脉夹层患者的科学预防、早期诊断和个性化治疗提供重要参考依据，具有重要的科学意义和临床应用价值。