孟德尔随机化研究铁死亡在非酒精性脂肪肝病的发生机制及作用研究

Mendelian randomization study on mechanism and role of ferroptosis in non-alcoholic fatty liver disease

目的 探讨孟德尔随机化研究铁死亡在非酒精性脂肪肝病的发生机制及作用。方法 基于铁死亡与非酒精性脂肪肝病的全基因组关联研究结果数据,采用IVW和MR-Egger两种两样本MR方法评估了包括:氧化应激、脂质过氧化、生长因子、趋化因子、炎性因子、肿瘤坏死因子及其他多个细胞因子与铁死亡和非酒精性脂肪肝病的因果关系,并采用多种方法完成其多效性检验。结果 确定氧化应激、脂质过氧化及炎性因子的效应值评估需要选择MR-Egger回归方法进行干预,其余参数均选择IVW为主要方法进行效应值统计。同时,入组的铁死亡相关的细胞因子对非酒精性脂肪肝的I2GX>0.9,使得该方法使用时不需要矫正偏差;铁死亡与NAFLD显著相关,铁死亡能通过脂质过氧化及炎症反应等,增加NAFLD的发生(IVW:OR=1.03,95%CI:1.01~1.04);趋化因子CXCL19与肝细胞因子对NAFLD的发生存在潜在效应;Q检验P与MR-Egger回归方法截距P>0.05,说明MR分析结果未见多效应性偏差。结论 从基因层面而言,铁死亡能直接参与非酒精性脂肪肝的发生和发展,并伴有脂质过氧化及炎性反应,造成肝脏细胞变性,亦可为临床治疗提供新的思路,但仍需要进一步研究来全面的评估其相关性。

Objective To explore the mechanism and role of ferroptosis in the pathogenesis of non-alcoholic fatty liver disease(NAFLD)under Mendelian randomization.Methods Based on the genome-wide association study data of ferroptosis and non-alcoholic fatty liver disease,two sample MR methods of IVW and MR-Egger were used to evaluate the causal relationship with ferroptosis and non-alcoholic fatty liver disease,including oxidative stress,lipid peroxidation,growth factors,chemokines,inflammatory factors,tumor necrosis factor,and multiple other cytokines.Multiple methods were used to complete their pleiotropy tests.Results The effect values of oxidative stress,lipid peroxidation,and inflammatory factors needed to select the MR Egger regression method for intervention,while IVW was the main method for effect value statistics for other parameters.Meanwhile,the I2GX of iron death related cytokines to non alcoholic fatty liver disease was greater than 0.9,making it unnecessary to correct deviations when using this method.Iron death was significantly correlated with NAFLD,which could increase the occurrence of NAFLD through lipid peroxidation and inflammatory reactions(IVW:OR=1.03,95%CI:1.01-1.04).There was a potential effect of chemokine CXCL19 and liver cytokines on the occurrence of NAFLD;The P value of Q-test and intercept of MR Egger regression method were over 0.05,indicated that there was no multiple effect bias in the MR analysis results.Conclusions From a genetic perspective,ferroptosis can directly participate in the occurrence and development of non-alcoholic fatty liver disease,accompanied by lipid peroxidation and inflammatory reactions,leading to liver cell degeneration.It can also provide new ideas for clinical treatment,but further research is needed to comprehensively evaluate its correlation.