新疆维吾尔族、汉族非酒精性脂肪肝甘油三酯代谢基因常见、稀有变异的高通量测序筛选

Nonalcoholic fatty liver disease (NAFLD) is due to the abnormal deposition of triglycerides, and associated with obesity, type 2 diabetes, dyslipidemia, hypertension and other symptoms of metabolic syndrome. Individual differences in genetic background was the important mechanism of NAFLD, lower triglycerides decomposition was the important cause leading to the fatty liver, liver triglyceride decomposition related gene polymorphism was of great significance in the pathogenesis of NAFLD. PNPLA3, APOC3 was an important adjusted factor of triglyceride catabolism. The result still has considerable controversy APOC3 gene polymorphism with NAFLD relevance. Previous studies found that prevalence of NAFLD in Uyghur was significantly higher than that of the Han population, and Polymorphism of triglyceride metabolism genes were related with NAFLD in Chinese Han, but there was not relationship in Uyghur population. The differences maybe were caused by group differences. Based on the hypothesis, the study from polymorphism of triglyceride decomposition related genes and rare mutation, using the next generation sequencing technology to detect the correlation between NAFLD and the polymorphism of triglyceride decomposition related gene and rare mutation in Uyghur and Han Chinese population polymorphism, and explore NAFLD molecular genetic mechanism in order to provide important basis for prevention.

非酒精性脂肪性肝病是由于体内甘油三酯的异常沉积，与2型糖尿病、代谢综合征密切相关。甘油三酯分解降低是造成肝脏脂肪堆积导致脂肪肝的重要原因，甘油三酯分解相关基因多态性对NAFLD发病机制具有重要意义。PNPLA3、APOC3等甘油三酯代谢基因是调节甘油三酯分解代谢的重要因子，不同人群PNPLA3、ApoC3等基因多态性与NAFLD关联性仍存在较大争议。前期研究发现维吾尔族NAFLD患病率明显高于汉族，而汉族人群中NAFLD与甘油三酯代谢基因SNPs（rs2854116、rs2854117）具有相关性,但在维吾尔族人群中无显著的相关性。这些差异可能由群体特异性所导致。基于这些假说，本研究拟利用维吾尔族独特性遗传背景，从调控甘油三酯代谢通路基因多态性和稀有突变入手，采用高通量测序技术，筛查维吾尔族、汉族甘油三酯代谢通路基因多态性和稀有与NAFLD相关性，探讨NAFLD分子遗传机制。

非酒精性脂肪性肝病是由于体内甘油三酯的异常沉积，甘油三酯分解降低是造成肝脏脂肪堆积导致脂肪肝的重要原因，PNPLA3、ApoC3等甘油三酯代谢基因是调节甘油三酯分解代谢的重要因子。本研究采用高通量测序技术检测对维吾尔族、汉族NAFLD病例组及对照组间甘油三酯分解代谢重要基因外显子区域，发掘相关SNPs和稀有突变的等位基因及基因型分布及基因间交互作用；同时采用流行病学调查方法，通过问卷调查、体格检查、生化指标检测以及实时超声检测，分析维吾尔族、汉族NAFLD危险因素。结果发现4318名体检者的NAFLD总患病率为39.42%，维吾尔族NAFLD患病率（45.2%）高于汉族（36.1%），发现性别、年龄、体质指数、血压、高脂饮食、缺乏运动、血红蛋白浓度、血尿酸、空腹血糖、甘油三酯、胆固醇、低密度脂蛋白水平是发生非酒精性脂肪肝的主要危险因素。确定维吾尔族、汉族人群PNPLA3、ApoC3、ApoA5、MTHFR、FABP1、FABP2等基因多态性和稀有突变与NAFLD的相关性。确定PNPLA3-rs738409G、ApoA5-rs662799G、FABP1-rs1545224、MTHFR-rs1801133基因多态性位点是NAFLD危险因素，是NAFLD遗传易感性的重要因素。PNPLA3-rs738409与ApoA5-rs3135506、PNPLA3-rs738409与ApoA5-rs662799间存在交互作用，但与基因间互作树及互作图谱的结果不一致，ApoC3、ApoA5、PNPLA3基因间有互作效应还有待于进一步深入研究。为有效预防和诊治非酒精性脂肪性肝病提供重要基础，为探索适合维吾尔族人群NAFLD的防治策略提供理论依据。