代谢物介导免疫细胞参与非酒精性脂肪性肝病的发生: 一项多变量孟德尔随机化分析

Metabolites mediate immune cells to participate in the occurrence of non-alcoholic fatty liver disease: a multivariate Mendelian randomization analysis

摘要

目的 探讨免疫细胞与代谢物在非酒精性脂肪性肝病 (NAFLD) 发病机制中的独立因果关系, 同时关注代谢物在免疫细胞变化引发 NAFLD 中的介导作用, 为 NAFLD 发病机制的深入研究奠定基础。方法 通过孟德尔随机化 (MR) 分析筛选与 NAFLD 相关的免疫细胞和代谢物。 然后, 分别进行 MR 获得相应的 beta 值。 最后计算直接效应、 中介效应和效应比值。结果 获得与 NAFLD 发病相关的共 4 种免疫细胞和 22 种代谢物, 基于单核苷酸多态性预测的免疫细胞 “初始 CD4⁺T 细胞占 CD4⁺T 细胞百分比 (Naive CD4⁺%CD4⁺) ” 与 NAFLD 风险增加有关, 且 8.96%的风险是通过代谢物 “孕三醇二硫酸盐 (Pregnenetriol disulfate) ” 的水平介导的。结论 通过 MR 分析确定了免疫细胞和代谢物与 NAFLD 之间的密切联系, 其中 “Naive CD4⁺%CD4⁺” 的增加可能通过提高的 “Pregnenetriol disulfate” 水平来促进 NAFLD 的发展。

Abstract

Objective To investigate the independent causal relationship between immune cells and metabolites in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), and to pay attention to the mediating role of metabolites in NAFLD caused by immune cell changes, so as to lay the foundation for further research on the pathogenesis of NAFLD. Methods The immune cells and metabolites associated with NAFLD were screened by Mendelian randomization (MR) analysis. Then, MR was performed separately to obtain the corresponding beta values. Finally, the direct effect, mediation effect and effect ratio were calculated. Results Our study obtained 4 types of immune cells and 22 types of metabolites related to the pathogenesis of NAFLD. The immune cell “Naive CD4⁺%CD4⁺” predicted based on single nucleotide polymorphisms was associated with an increased risk of NAFLD, and 8.96% of the risk was mediated by levels of “Pregnenetriol disulfate”. Conclusion This study identified a close connection between immune cells and metabolites and NAFLD through MR analysis, in which the increase of “Naive CD4⁺%CD4⁺” may promote the development of NAFLD through increased “Pregnenetriol disulfate” levels.

关键词

非酒精性脂肪性肝病 / 非酒精性脂肪性肝炎 / 孟德尔随机化 / 代谢物 / CD4⁺T 细胞 / Naive CD4⁺T 细胞

Key words

non-alcoholic fatty liver disease / non-alcoholic steatohepatitis / Mendelian randomization / metabolites / CD4⁺T cells / Naive CD4⁺T cells

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基金资助

国家自然科学基金面上项目(81970512)