烟雾病和颅内动脉狭窄闭塞患者致病基因的遗传流行病学研究

Moyamoya disease (MMD) is a chronic idiopathic disorder characterized by steno-occlusive lesions around the terminal portions of the internal carotid arteries accompanied by abnormal collateral vessels. While the incidence of MMD is worldwide, it is particularly high in East Asian countries. MMD is known to cause stroke in neonates and children. The previous studies have demonstrated that the genetic variant ring finger protein 213 (RNF213) p.R4810K was common to MMD and intracranial artery stenosis/occlusion. The prevalence of the risk allele p.R4810K in RNF213 in Chinese patients was significantly lower than that in Japanese and Korean patients, suggesting a complex genetic heterogeneity in Chinese patients with MMD. The purpose of this study is to discover the common causative gene for MMD with various ethnicities by multistage study. First, exome analysis and genome-wide linkage analysis will be conducted to identify the causative gene for Chinese familial MMD. Next, the causative gene identified in Chinese familial MMD will be validated in Chinese sporadic MMD and intracranial artery stenosis/occlusion. Furthermore, the causative gene identified in Chinese familial MMD will be also validated in Japanese and Korean MMD patients. Finally, the interaction of newly identified causative gene and RNF213 will be analyzed by bioinformatics to elucidate the etiology and mechanisms of MMD and intracranial artery stenosis/occlusion with various ethnicities. Our findings might be applied in early prevention, diagnosis and molecular targeted treatment of MMD and intracranial artery stenosis/occlusion.

烟雾病是以双侧颈内动脉末端慢性狭窄或闭塞、继发颅底异常血管网形成为特征的脑血管病。烟雾病在全球均有报道，但在东亚人群高发，是导致新生儿和儿童中风的危险因素。RNF213 p.R4810K是东亚烟雾病和颅内动脉狭窄闭塞共同致病基因，但中国患者致病基因携带率远低于日本韩国患者，提示中国烟雾病存在复杂的遗传异质性。本课题拟开展多阶段研究，探索不同种族烟雾病和颅内动脉狭窄闭塞的致病基因。首先，在中国汉族家族烟雾病中开展外显子组及基因组范围连锁分析，探索中国汉族烟雾病致病基因。其次，在中国汉族散发烟雾病及颅内动脉狭窄闭塞中验证探索阶段发现的致病基因。再次，在日本韩国和欧洲不同种族烟雾病中进一步验证探索阶段发现的致病基因。最后，分析新鉴定的致病基因与RNF213的交互作用，阐明不同种族烟雾病及颅内动脉狭窄闭塞的病因及发病机制。本研究将为烟雾病以及脑血管狭窄闭塞的早期预防、诊断及分子治疗奠定理论基础。

烟雾病是以双侧颈内动脉末端慢性狭窄或闭塞、继发颅底异常血管网形成为特征的脑血管病。烟雾病在全球均有报道，但在东亚人群高发，是导致新生儿和儿童中风的危险因素。本研究共募集182个烟雾病家系，散发烟雾病3000人，以及健康对照3000人。开展烟雾病致病基因RNF213 p.R4810K荟萃分析和病例对照相关分析；开展RNF213 p.R4810K基因型与临床表型相关分析；开展烟雾病外显子组测序分析；最后开展烟雾病致病基因的病例对照相关分析。本研究证明RNF213 p.R4810K是东亚不同种族烟雾病、颅内动脉狭窄闭塞以及类烟雾病的共同致病基因，扩大了RNF213 p.R4810K相关疾病谱。通过大样本病例对照分析证明RNF213 p.R4810K是中国烟雾病的主要致病基因。证明RNF213 p.R4810K可以预测中国烟雾病患者的发病年龄以及疾病的严重程度。鉴定了非RNF213 p.R4810K携带患者致病基因，提示同型半胱酸代谢相关基因可能在烟雾病病因及其发病机制中起重要作用。本研究将为烟雾病以及脑血管狭窄闭塞的早期预防、诊断及分子治疗提供理论依据。