水果摄入状态与非酒精性脂肪肝病的双向孟德尔随机化分析

Causal associations between fruit intake and non-alcoholic fatty liver disease: a mendelian randomization study

摘要

目的 采用双向、两样本孟德尔随机化（MR）方法探讨水果摄入状态与非酒精性脂肪肝病（NAFLD）之间的双向相关关系。方法 选择IEU OpenGWAS和finngen数据库，以单核苷酸多态性为工具变量，暴露因素为新鲜水果摄入、纯果汁摄入和水果干摄入，结局指标为NAFLD；为避免反向因果关系影响，将NAFLD作为暴露因素，新鲜水果摄入、纯果汁摄入和水果干摄入作为结局指标，进行反向MR分析。采用MR-Egger、加权中位数、逆方差加权（IVW）、简单模式和加权模式5种方法进行两样本MR分析，其中，以IVW法作为主要分析方法，分析水果摄入状态与NAFLD之间的相关关系。采用Cochran’s Q检验检测异质性；MR多效性残差和离群值（MR-PRESSO）检验、MR-Egger回归检测水平多效性；“留一法”分析结果是否稳健；漏斗图评估是否对称。结果 正向MR分析的IVW分析结果显示新鲜水果摄入、纯果汁摄入与NAFLD之间不存在相关关系，水果干摄入与NAFLD之间存在负相关关系［OR=0.426，95%CI：0.208～0.873，P=0.020］，敏感性分析表明，孟德尔分析结果不存在异质性和水平多效性，留一法分析显示孟德尔分析结果稳健；反向MR分析的IVW分析结果显示NAFLD与新鲜水果摄入、纯果汁摄入、水果干摄入之间均不存在相关关系，MR-Egger回归、简单模式、加权模式、加权中位数分析结果也支持该结论。结论 利用双向、双样本MR分析方法从遗传学层面推断水果干摄入与NAFLD之间存在相关关系，水果干摄入可能是NAFLD的重要保护因素，适量的水果干摄入可能对NAFLD患者有益。

Abstract

Objective To explore the bidirectional correlation relationship between fruit intake state and non-alcoholic fatty liver disease (NAFLD) using a bidirectional two-sample Mendelian randomization (MR) study. Methods The IEU OpenGWAS and finngen databases were selected. Single nucleotide polymorphisms (SNPs) were used as instrumental variables. Exposure factors included fresh fruit intake, pure fruit juice intake, and dried fruit intake. The outcome measure was non-alcoholic fatty liver disease (NAFLD). To avoid the influence reverse causality, a reverse Mendelian randomization analysis was performed with NAFLD as the exposure factor, and fresh fruit intake, pure juice intake, and dried fruit intake as the outcome indicators. Two-sample Mendelian randomization analyses were conducted using five methods: MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode. The inverse variance weighted analysis was selected as the primary method to examine the causal relationship between fruit intake state and NAFLD. Cochran’s Q test assessed heterogeneity; the Mendelian randomization multi-effect residuals and outliers (MR-PRESSO) test and MR-Egger regression tested for level multi-effect; the “leave-one-out” method evaluated robustness; and the funnel plot assessed symmetry. Results The IVW analysis from the forward MR indicated that there was no association between fresh fruit intake and pure fruit juice intake with non-alcoholic fatty liver disease (NAFLD). However, dried fruit intake showed a negative correlation with NAFLD [OR=0.426, 95%CI: 0.208-0.873, P=0.020]. Sensitivity analyses indicated no heterogeneity or horizontal pleiotropy in the Mendelian randomization results, and the leave-one-out analysis demonstrated the robustness of the Mendelian randomization findings. Conversely, the IVW analysis from reverse MR indicated that there was no correlation between non-alcoholic fatty liver disease and intake of fresh fruit, pure juice, or dried fruit, with MR-Egger, simple model, weighted model, and WMM analysis further supporting this outcome. Conclusion Utilizing a bidirectional two-sample MR analysis approach from a genetic perspective, this study infers a causal relationship between dried fruit intake and NAFLD. Consuming dried fruits may serve as an important protective factor against non-alcoholic fatty liver disease, and moderate intake of dried fruits may be beneficial for patients with NAFLD.

关键词

水果摄入状态 / 非酒精性脂肪肝病 / 孟德尔遗传 / 单核苷酸多态性

Key words

fruit intake state / non-alcoholic fatty liver disease / Mendelian inheritance / single nucleotide polymorphism

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基金资助

上海市金山区卫健委、区科委面上项目(JSKJ-KTMS-2024-04)