目的:已经观察到20-80%的非酒精性脂肪性肝病(NAFLD)具有血脂异常。然而,血脂异常对NAFLD影响的可能机制尚不清楚.孟德尔随机化(MR)用于研究血脂之间的关系,炎症因子,和NAFLD;还有,确定由白细胞介素-17(IL-17)和白细胞介素-1β(IL-1β)介导的脂质和NAFLD之间的作用的比例。
方法:性状的汇总统计来自最新和最大的全基因组关联研究(GWAS)。英国生物银行提供了脂质统计摘要,其中包括多达500,000欧洲血统的参与者。NAFLDGWAS汇总统计数据来自FinnGen生物库,其中包括218,792名欧洲血统参与者的总样本量。为了全面了解脂质如何影响NAFLD,用两个样品进行MR。多变量MR在调整炎症因子后确定血脂对NAFLD的直接影响,即IL-1β,白细胞介素-6(IL-6),白细胞介素-16(IL-16),IL-17和白介素-18(IL-18);这些脂质包括HDL胆固醇(HDL-C),LDL胆固醇(LDL-C),甘油三酯(TG),载脂蛋白A1(ApoA1),载脂蛋白B(ApoB)。为了确定MR影响,对每个Wald比率进行逆方差加权(IVW)荟萃分析,同时还进行了其他方法的敏感性分析。
结果:我们发现遗传预测的TG水平与NAFLD的45.5%升高的风险之间存在正相关,而遗传预测的IL-1β[(IVW:OR1.315(1.060-1.630),p=0.012)和IL-17[(IVW:或1.468(1.035-2.082),p=0.032]与NAFLD风险增加31.5%和46.8%呈正相关,分别。此外,TG与IL-1β风险增加10.5%和IL-17风险增加17.3%呈正相关。IL-17和IL-1β介导的比例分别为2.6%,3.1%,14.1%。
结论:遗传预测的TGs,IL-1β,IL-17与NAFLD风险增加呈正相关,有证据表明IL-1β和IL-17介导的TG对NAFLD风险有影响。它表明早期饮食管理,体重管理,高脂血症患者应进行降脂和抗炎治疗以预防NAFLD。
OBJECTIVE: 20-80% of Nonalcoholic Fatty Liver Disease (NAFLD) have been observed to have dyslipidemia. Nevertheless, the probable mechanism of dyslipidemia\'s effect on NAFLD remains unclear. Mendelian randomization (MR) was utilized to investigate the relationship between lipids, inflammatory factors, and NAFLD; and also, to determine the proportion mediated by interleukin-17(IL-17) and interleukin-1β(IL-1β) for the effect between lipids and NAFLD.
METHODS: Summary statistics of traits were obtained from the latest and largest genome-wide association
study (GWAS). The UK Biobank provided a summary of lipid statistics, which comprised up to 500,000 participants of European descent. And NAFLD GWAS summary statistics were obtained from the FinnGen Biobank which included a total sample size of 218,792 participants of European ancestry. In order to gain an overall picture of how lipids affect NAFLD, MR with two samples was carried out. Multivariable MR determined lipids direct effects on NAFLD after adjusting for inflammatory factors, namely IL-1β, interleukin-6(IL-6), interleukin-16(IL-16), IL-17, and interleukin-18(IL-18); those lipids comprise HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). For the purpose of determining the MR impact, an inverse variance weighted (IVW) meta-analysis of each Wald Ratio was carried out, while other methods were also performed for sensitivity analysis.
RESULTS: We discovered a positive association between genetically predicted TGs levels and a 45.5% elevated risk of NAFLD, while genetically predicted IL-1β [(IVW: OR 1.315 (1.060-1.630), p = 0.012) and IL-17 [(IVW: OR 1.468 (1.035-2.082), p = 0.032] were positively associated with 31.5% and 46.8% increased risk of NAFLD, respectively. Moreover, TG was positively associated with 10.5% increased risk of IL-1β and 17.3% increased risk of IL-17. The proportion mediated by IL-17 and IL-1β respectively and both was 2.6%, 3.1%, 14.1%.
CONCLUSIONS: Genetically predicted TGs, IL-1β, and IL-17 were positively associated with increased risk of NAFLD, with evidence that IL-1β and IL-17 mediated TGs effect upon NAFLD risk. It indicated that early diet management, weight management, lipid-lowering and anti-inflammatory treatment should be carried out for patients with hyperlipidemia to prevent the NAFLD.