血脂水平介导饮食与子宫内膜异位症的因果关系：一项孟德尔随机化研究

The Causal Relationship between Blood Lipid Levels Mediating Diet and Endometriosis: A Mendelian Randomized Study

摘要: 研究背景：子宫内膜异位症(EMs)是一种雌激素依赖性的慢性炎症性疾病，影响约10%的育龄期女性。EMs症状的复杂性和不典型性严重影响患者的生理和心理健康并对社会经济造成沉重的负担。然而EMs的发病机制和有效的干预措施目前尚不完全清楚。饮食作为重要干预措施在多种慢性疾病中发挥作用，然而，关于饮食在EMs中的作用相关研究较少且多为观察性研究。孟德尔随机化(MR)利用遗传变异作为工具变量可以弥补传统观察性研究的不足，因而被广泛应用于探索可改变的暴露与疾病之间的因果关系。研究方法：本研究利用双向双样本MR分析方法探究饮食与EMs之间的因果关系。分别从IEU数据库和芬兰基因联盟中获取与饮食和EMs有关的全基因组关联研究(GWAS)数据。将基因位点显著性阈值设定为P < 5 × 10⁻⁶，并通过去除连锁不平衡(LD)及剔除与结局相关的混杂SNP等方法严格筛选出代表暴露的工具变量(IV)后进行MR分析。进一步地，利用中介MR分析探究二者之间潜在的中介因素，探究了血脂在饮食和EMs中的中介效应。为了评估研究结果的稳定性，还进行了多种敏感性分析。研究结果：本研究主要基于IVW方法，有力地证明了干果和油性鱼类的摄入与EMs之间存在因果关系，以及TG在饮食和EMs之间的中介作用。具体而言，在所有饮食因素中，干果摄入(OR = 0.72, 95% CI: 0.56~0.93, P = 0.01)和油性鱼类摄入(OR = 0.80, 95% CI: 0.66~0.97, P = 0.02)与EMs发生风险降低有关。血脂水平与EMs之间的因果关系发现TG是EMs发生的危险因素(OR = 1.15, 95% CI: 1.07-1.23, P < 0.01)。进一步发现，干果(OR = 0.81, 95% CI: 0.75~0.88, P < 0.01)和油性鱼类摄入(OR = 0.86, 95% CI: 0.81~0.91, P < 0.01)均可降低TG水平，且中介MR分析显示TG在干果和油性鱼类摄入对EMs的保护性作用中均起到中介效应，中介比例分别为9% (P = 0.001)和10% (P = 0.002)。研究结论：本研究利用MR分析发现干果和油性鱼类的摄入与EMs发生风险降低有关。血脂水平尤其是TG水平与EMs的发生风险增加有关。干果和油性鱼类对EMs的保护作用部分是通过降低TG水平实现的。

Abstract: Background: Endometriosis (EMs) is an estrogen-dependent chronic inflammatory disease with a high prevalence, affecting approximately 10% of women of reproductive age. The complexity and atypical nature of EMs symptoms severely impact patients’ physical and mental health and impose a significant socioeconomic burden. However, the pathogenesis and effective interventions for EMs remain incompletely understood. Diet, as an important intervention, plays a role in various chronic diseases. Nevertheless, research on the role of diet in EMs is limited and predominantly observational. Mendelian randomization (MR), which uses genetic variants as instrumental variables, can address the limitations of traditional observational studies and is widely used to explore causal relationships between modifiable exposures and diseases. Methods: This study employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal relationship between diet and EMs. Genome-wide association study (GWAS) data related to diet and EMs were obtained from the IEU database and the Finnish Gene Consortium, respectively. Genetic loci with a significance threshold of P < 5 × 10⁻⁶ were selected, and instrumental variables (IVs) representing exposures were rigorously screened by removing linkage disequilibrium (LD) and excluding SNPs associated with confounding factors. Furthermore, mediation MR analysis was conducted to explore potential mediating factors between diet and EMs, specifically focusing on blood lipids. Finally, various sensitivity analyses were performed to evaluate the robustness of the findings. Results: Based primarily on the IVW method, this study provided strong evidence for a causal relationship between the intake of dried fruits and oily fish and EMs, as well as the mediating role of triglycerides (TG) in the relationship between diet and EMs. Specifically, among all dietary factors, the intake of dried fruits (OR = 0.72, 95% CI: 0.56~0.93, P = 0.01) and oily fish (OR = 0.80, 95% CI: 0.66~0.97, P = 0.02) was associated with a reduced risk of endometriosis. Subsequently, we explored the causal relationship between blood lipid levels and EMs and found that TG is a risk factor for EMs (OR = 1.15, 95% CI: 1.07~1.23, P < 0.01). Further analysis revealed that both dried fruit (OR = 0.81, 95% CI: 0.75~0.88, P < 0.01) and oily fish intake (OR = 0.86, 95% CI: 0.81~0.91, P < 0.01) could reduce TG levels. Mediation MR analysis showed that TG mediated the protective effects of dried fruits and oily fish on EMs, with mediation proportions of 9% (P = 0.001) and 10% (P = 0.002), respectively. Conclusions: This study, using MR analysis, found that the intake of dried fruits and oily fish is associated with a reduced risk of EMs. Blood lipid levels, particularly TG, are associated with an increased risk of endometriosis. The protective effects of dried fruits and oily fish on EMs are partially mediated by reducing TG levels.