TM6SF2 rs58542926多态性与青岛汉族人群非酒精性脂肪性肝病发病风险的相关性及分子机制研究

Association between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease in Qingdao Han Population and molecular mechanism

目的探讨青岛地区汉族人群中TM6SF2 rs58542926多态性与非酒精性脂肪性肝病(NAFLD)发病风险的相关性,并在细胞水平进一步探讨TM6SF2 167位点多态性影响脂质代谢的分子机制。方法纳入2016年10月-2017年11月于青岛市市立医院就诊的512例NAFLD患者(NAFLD组)及451例年龄及性别匹配的健康受试者(对照组)。采用聚合酶链式反应及基因型检测方法对TM6SF2 rs58542926位点进行基因型检测,计算各组基因型、等位基因频率,以及发生NAFLD的相对风险。构建稳定表达TM6SF2基因167位点突变型和野生型病毒的Hepa1-6细胞。检测表达TM6SF2突变型和野生型病毒的Hepa1-6细胞中胆固醇(TC)和三酰甘油(TG)的含量,以及固醇调节元件结合蛋白-1c(SREBP-1c)mRNA和蛋白的表达水平并进行比较。结果 TM6SF2 rs58542926位点各基因型和等位基因在NAFLD组与对照组的分布差异均有统计学意义(P<0.001)。与非携带者相比,T等位基因携带者发生NAFLD的危险度为2.327(95%CI:1.542～3.513,P<0.001)。与表达TM6SF2野生型病毒的Hepa1-6细胞相比,表达突变型病毒的Hepa1-6细胞具有更高的TC和TG含量(P<0.001),且SREBP-1cmRNA及蛋白表达水平亦明显增高(P<0.001)。结论青岛地区汉族人群的TM6SF2rs58542926多态性与NAFLD发病风险具有一定的相关性,TM6SF2 167位点突变型T等位基因可能通过上调SREBP-1c的表达而调节肝脏脂质代谢。

Objective To investigate the association between the TM6 SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease(NAFLD) in Qingdao Han Population, and the molecular mechanism of TM6 SF2 167 locus polymorphism affecting lipid metabolism. Methods We genotyped a cohort of NAFLD patients(NAFLD group) treated in Qingdao Municipal Hospital from Octorber 2016 to November 2017 and 451 healthy controls(control group) matched for age and sex by polymerase chain reaction and direct sequencing. Distribution of genotypes and allele frequencies of TM6 SF2 rs58542926 and the relative risk of NAFLD were assessed. In addition, we concentrated the lentivirus of TM6 SF2-mutant type and TM6 SF2-wild type and transfected into Hepa1-6 cells. The concentration of lipid indicators and the expressions of SREBP-1 c mRNA and protein were determined.Results There were significant differences in the genotype and allele frequencies of TM6 SF2 rs58542926 polymorphism between the NAFLD and control group(P<0.001). Carriers of T allele had significantly increased susceptibility to NAFLD(OR=2.327,95%CI: 1.542-3.513, P<0.001). Total cholesterol(TC) and triglyceride(TG) contents of the TM6 SF2-mutant type group were both increased to high levels when compared with the TM6 SF2-wild type group(P<0.001). Furthermore, the expression levels of sterol regulatory element-binding transcription factor 1 c(SREBP-1 c) mRNAs and protein of the TM6 SF2-mutant type group were significantly increased when compared with either of the TM6 SF2-wild type group(P<0.001). Conclusions The TM6 SF2 rs58542926 polymorphism is associated with risk of NAFLD in Qingdao Han Population. Furthermore, the mutant T allele at TM6 SF2 167 locus may regulate the hepatic lipid metabolism through increasing the expression of SREBP-1 c.