补体系统与葡萄膜炎的遗传易感性研究及表型相关性分析

Uveitis is a group of common blinding eye diseases, which causes substantial visual impairment and presents challenges to clinical treatment. The exact pathogenesis of uveitis has not been well defined, Immune mechanisms have long been considered as playing a central role in the pathogenesis of uveitis. Complement system, a key component of innate immunity and is involved in modulating various immune and inflammatory responses, which has become a hot area of research in recent years. A recent study by using animals has demonstrated that the activation of complement system is critical for the development of uveitis, but few researches have been performed on the genetic associations between them. Based on this topic, the applicant has performed a series of investigations, our results, for the first time, provide novel findings that complement factors CFH and CFB, involved in the alternative complement pathway, were identified to be associated with human uveitis. In addition, some polymorphisms were identified as clinical markers associated with specific disease phenotype. Moreover, joint effects between their risk genotypes conferring a strongly increased risk to uveitis were found. Notably, the genetic influence could be gender-specific. Significant advancements have been made in this field.. As a follow-up study, we will take this opportunity, based on large sample size, by using next-generation sequencing technologies and designing targeted gene probe, to fully investigate the genetic susceptibility of uveitis with complement factors. From a novel view to clarify the molecular mechanism of uveitis, provide new targets for the clinical diagnosis and treatment.

葡萄膜炎是一类常见的致盲眼病，视力损害严重，治疗棘手。确切机制尚未阐明，多认为与内源性的免疫调控失衡及遗传易感性相关。补体系统，作为人类先天性免疫系统的一部分，广泛参与了机体微生物防御反应及免疫调节，是近年来研究热点。最近一项关于葡萄膜炎的动物研究发现，补体系统的调控失活在其发病中起着至关重要的作用。但二者间的遗传相关性国内外尚无报道，基于此，本申请人做了大量的前期研究，首次发现并提出，补体旁路因子CFH与CFB的基因多态性与人类葡萄膜炎发病相关，表现为性别敏感性差异，且二者间存在累加效应，同时发现了多个可能的临床表型标记物，在此领域上取得较大成果。. 本项目作为后续研究，将以此为契机，在大样本临床病例基础上，利用新一代高通量测序技术，设计靶向性基因探针，全面涵盖补体系统重要调控因子的遗传信息，对葡萄膜炎的遗传易感性做深入研究。从新的视角阐明其分子机制，为临床诊治提供新靶点。

葡萄膜炎，作为一种常见的眼科炎症疾病，其发病机制尚未阐明，临床表现多样，复发率高，治疗棘手，向来为眼科学界顽疾之一。我们的前期研究首次在基因水平上提出补体调控因子与葡萄膜炎发病相关，因子间存在基因累加效应，一个与前葡萄膜炎复发频次相关的临床标记物被确定，为补体系统在葡萄膜炎发病中的调控作用研究提供了理论依据。但就目前结果来看，还有诸多不足，相关研究还有待完善和确定。.我们的主要研究目标为：扩大临床样本量，汇总并建立葡萄膜炎临床资料库。进一步筛选及定位与疾病密切相关的补体因子，找寻葡萄膜炎临床标记物，全面展现补体系统与葡萄膜炎的关系，从“分子视觉”角度探索选择性补体通路调控作为葡萄膜炎新型治疗靶点的可能性。.我们发现其多态位点rs1048709与非感染性中后葡萄膜炎显著相关，该相关性具有明显的性别敏感性差异；随后，亚组分析显示，该位点与疾病亚型VKH显著相关，表现出特异性效应。与此同时，我们发现：C5-rs17611与葡萄膜炎发病相关, 且表现性别敏感性差异。C3，作为补体调控的核心因子，参与了三条主要调控通路，我们的课题采用了多种分析方法，如总体分析，亚组分析，回归分析，单倍体型分析等，数据显示：C3基因多态性与葡萄膜炎，包括前葡萄膜炎及非感染性中后葡萄膜炎均无明显相关性。.综上，我们的研究从基因-分子-通路水平绘制“整体”遗传谱系，进而鉴明补体因子及其所在调控通路在炎症性眼病的参与程度，为后续研究打下坚实基础。