染色质重塑关键复合体SWI/SNF基因遗传变异与肝癌易感性及机制研究

Mating type switch/sucrose non-fermenting (SWI/SNF) complex is a core factor for chromatin-remodeling that utilize energy of ATP hydrolysis to mobilize nucleosomes, and modulate gene transcription. Due to its pivotal role in regulation of multiple cellular processes, including proliferation, differentiation, and apoptosis, SWI/SNF complex has been implicated in development of hepatocellular carcinoma. Herein, a two-stage case-control study will be conducted in two independent populations enrolled from Shunde and Wuhan regions, respectively, to investigate the association between hepatocellular carcinoma susceptibility and the variants in SWI/SNF key genes, including SNF5, BRG1, BRM, ARID1A, ARID2, and PBRM1. Potential gene-gene and gene-environment interactions involving in hepatocellular carcinoma development will be also explored by a comprehensive statistical strategy. Basis on preliminary bioinformatics analysis, in-depth molecular biological experiments will be performed to explore the mechanism underlying the genetic variants associated with hepatocellular carcinoma. This study will identify the causal variants of SWI/SNF for hepatocellular carcinoma development, and will provide valuable clues to illustrate the mechanism of hepatocellular carcinoma development. Furthermore, causal variants revealed by this study can be used as genetic markers for risk assessment and early screening of hepatocellular carcinoma.

SWI/SNF复合体是介导染色质重塑过程的核心因子，通过利用ATP水解释放的能量动员核小体，调控基因转录，广泛参与调节细胞增殖、分化、凋亡等进程，被认为在肝癌发生发展过程中起重要作用。本项目拟采用两阶段关联性研究策略，分别在广东顺德和湖北武汉地区的独立病例-对照人群中对SWI/SNF复合体的关键基因SNF5、BRG1、BRM、ARID1A、ARID2及PBRM1的遗传变异进行检测，系统探讨其与中国人群肝癌易感性的关联性；采用综合性统计策略剖析基因-基因、基因-环境的交互作用对肝癌发生发展的影响；在初步生物信息学分析的基础上对与肝癌易感性相关的遗传变异进行生物学机制的深入分析，以鉴定病因性变异，为进一步揭示肝癌发病机制提供理论依据，为肝癌风险评估、早期筛检等预防医学实践提供遗传标志物。

ATP依赖的染色质重塑SWI/SNF复合体是调控基因转录的核心因子，其多个亚基编码基因已被认为是肝癌的重要易感基因。本项目采用分子流行病学、生物信息学和分子生物学方法，在广东顺德地区、武汉地区和北京地区的肝癌病例-对照人群中，系统探讨SWI/SNF复合体关键基因的常见遗传变异对肝癌易感性的影响及相关机制。项目发现：（1）ARID1B基因的rs73013281变异与肝癌发病风险密切相关，与携带rs73013281CC基因型者相比，CT/TT基因型携带者的肝癌发病风险增加70%（显性模型OR=1.70, 95% CI=1.03-2.80）。(2)rs73013281变异与运动之间的交互作用对肝癌发病有重要影响，缺乏运动可增强rs73013281T等位基因的促肝癌效应，而规律运动则可削弱T等位基因的有害效应。（3）双荧光素酶报告基因实验显示，rs73013281定位于ARID1B基因的启动子区，含T等位基因重组质粒的报告基因表达量显著高于C等位基因重组质粒，说明rs73013281变异可影响ARID1B基因转录活性，干扰SWI/SNF复合体靶基因的表达，进而促进肝癌发生。（4）BRG1基因的rs11879293变异与肝癌风险存在统计学关联，每增加一个rs11879293A等位基因的携带，肝癌发病风险降低27%（加性模型OR=0.73,95% CI=0.62-0.87），并且rs11879293与乙肝病毒感染之间存在显著的交互作用（相乘、相加交互P值=0.008,0.003）。但rs11879293为内含子变异，且在与rs11879293高度连锁不平衡区域中，尚未发现与肝癌关联的常见变异，rs11879293与肝癌的统计学关联的生物学意义尚待深入挖掘。本项目所识别的rs73013281变异可作为构建肝癌风险预测模型和识别易感人群的遗传标志物，所发现的rs73013281与运动之间的交互模式可为肝癌预防措施制定提供学术参考。