【作者】 徐静；

【导师】 宣世英；

【作者基本信息】 青岛大学 ， 内科学， 2012， 硕士

【摘要】 目的非酒精性脂肪性肝病(Non-alcoholic fatty liver disease NAFLD)已成为西方发达国家中最常见的慢性肝脏疾病之一。目前NAFLD被认为是与遗传因素、环境因素、心理因素等相关的多因素疾病,而且是一种高度遗传的疾病。近年来,国外许多研究指出PNPLA3基因多态性与NAFLD的遗传易感性及肝损害有关系,但是目前尚缺乏相对大样本中国地区PNPLA3基因多态性与NAFLD的相关性研究,因此我们分析青岛地区汉族人群中PNPLA3基因多态性的特征,探讨在中国人群中PNPLA3基因多态性与非酒精性脂肪性肝病的遗传易感性的相关性。方法本研究纳入NAFLD患者315例和健康对照组336例,采集其病史及生化结果资料,全血中提取DNA,采用聚合酶链反应(PCR)、基因测序方法检测NAFLD组及对照组中PNPLA3基因多态性的序列片段,根据其序列片段确定其基因型。通过Hardy-weinbeurg遗传平衡定律分析NAFLD组与对照组各基因型是否具有群体代表性,基因变异及NAFLD有关的因素之间的关系通过非条件Logistic回归分析。采用SPSS11.5软件进行统计学分析。结果中国汉族人群中,存在PNPLA3基因rs738409(I148M)多态性,rs738409 G等位基因频率分布在NAFLD(65.40%)与正常对照组(33.18%)、NASH组(71.87%)与SS组(56.47%)中比较差异均有统计学意义(P<0.05)。非条件Logistic回归分析显示：148GG基因携带者与148CC基因携带者相比较,前者发生NAFLD的比值比(OR)为3.81(95%CI：3.03～4.79,P<0.05),发生NASH的OR为1.97(95%CI=1.41-2.75, P<0.05)。PNPLA3基因rs738409多态性与血清ALT、γ-GT水平有关(P<0.05),对NASH组分层分析,148GG基因型BMI、ALT、FINS均高于148CC基因型(P<0.05),血清HDL水平低于148CC基因型和148GC基因型(P<0.05),这些结果提示等位基因G与肝脏炎症和肝脏脂肪增加有相关性。结论在中国汉族人群中,PNPLA3基因I148M多态性与NAFLD的遗传易感性相关,是决定NAFLD个体遗传易感性的重要因素。更多还原

【Abstract】 Objective:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. The etiology is believed to be multifactorial with genetic, environmental and psychosocial components, in particular genetic factors. Recently, multiple studies have revealed the gene polymorphism of the PNPLA3 rs738409 (I148M) is closely linked to the genetic susceptibility and progress of liver damage. But there was lack of large samples in china, so we analyzed the Han population’s polymorphism features in PNPLA3 gene of Qingdao, Shandong Province, to explore the relationship betweetn PNPLA3 gene and hereditariness to nonalcoholic fatty liver disease.Methods:The study included 315 cases of patients with NAFLD and 336 cases of healthy control subjects. We detected sequence fragments of PNPLA3 gene polymorphism both in NAFLD group and control group, by collecting their pathography and biochemical results, extracting DNA from whole blood, utilizing the polymerase chain reaction (PCR) and gene sequencing orderly, and according to their sequence fragments, we can determine their genotype. Whether each genotype of the NAFLD group and control group has group representation or not was based on Hardy-weinbeurg genetic equilibrium analysis, and the relationship between genetic mutations and NAFLD-related factors were analyzed by non-conditional Logistic regression. In addition, SPSS 11.5 software was used for statistical analysis.Results:There exists PNPLA3 gene polymorphism-rs738409(I148M) in Chinese population. Allele frequency distribution of rs738409 G were 65.40%,71.87% and 56.47% in patients with NAFLD, NASH and SS and 33.18% in control, respectively, which had statistical signification(P<0.05). Non-conditional Logistic regression showed, comparing with 148CC gene carriers, odds ratio of occurrence of NAFLD was 3.81(95% CI:3.03 to 4.79, P<0.05), and the odds ratio of occurrence of NASH OR was 1.97 (95% CI= 1.41-2.75, P<0.05) in 148GG gene carriers. Rs738409 polymorphism of the PNPLA3 gene is associated with the level of serum ALT、γ-GT. Through stratified analysis of NASH group, the BMI, ALT, and FINS of 148GG genotype are all higher than that of the 148CC genotype (P<0.05), while the serum HDL level of 148GG genotype is lower than that of both 148CC genotype and 148GC genotype (P<0.05), all of which suggests that allele G is linked with liver inflammation and the increase of liver fat.Conclusion:The results suggested that I148M, a PNPLA3 gene polymorphism, is associated with NAFLD hereditary susceptibility, which is a significant factor in determining NAFLD hereditary susceptibility, in Chinese population.更多还原