Associations between 1400 metabolites and subtypes of endometriosis: a two-sample Mendelian randomisation study

Endometriosis is a chronic inflammatory disease with a prevalence of approximately 10% in women of childbearing age. Metabolic pathways have been demonstrated by previous studies to be potential avenues for the development of new therapeutic strategies and may be used for early diagnosis of the disease. This study aimed to investigate the potential causal relationships between 1400 metabolites and various endometriosis subtypes using Mendelian randomisation (MR) analysis. Data from a genome-wide association study were analysed. MR analysis was performed using the inverse-variance weighted, MR-Egger, and weighted-median methods, accompanied by heterogeneity testing, sensitivity analysis, and pleiotropy analysis. Metabolic-pathway enrichment analysis was conducted on the preliminarily screened differential metabolites, and colocalisation analysis was subsequently performed for exposure–outcome pairs that remained causally associated after multiple-testing correction. After multiple-testing correction, only the glycerol-to-palmitoylcarnitine (C16) ratio reduced the risk of stage 1–2 endometriosis (PFDR = 0.045; odds ratio [OR], 0.737; 95% confidence interval [CI], 0.638–0.852) and pelvic peritoneal endometriosis (PFDR = 0.039; OR, 0.721; 95% CI, 0.619–0.841). Colocalisation analysis revealed that they did not share causal variant loci at the genetic level. No reverse causal associations were found in the reverse Mendelian analysis. Metabolic pathway enrichment analysis identified major metabolic pathways, including caffeine metabolism, glutathione metabolism, arginine biosynthesis, sphingolipid metabolism, pantothenate and CoA biosynthesis, plasmalogen synthesis, and biosynthesis of unsaturated fatty acids. Our study suggests potential causal relationships between metabolites and various endometriosis subtypes from an MR perspective. However, the limited number of associations that survived multiple-testing correction indicates that these findings are preliminary and require validation in larger cohorts. This exploratory analysis may contribute to advancing future research on metabolomics-based diagnosis, treatment, and prevention of endometriosis. Endometriosis is a condition in which tissues similar to the uterine lining grow outside the uterus. It affects approximately 1 in 10 reproductive-age women and can cause pain and fertility problems. In this study, we investigated whether certain natural substances in the blood, called metabolites, play a role in different forms of endometriosis. We used genetic data to test over 1,000 metabolites and found that only the glycerol-to-palmitoylcarnitine ratio showed a meaningful link. A higher ratio may reduce the risk of mild or pelvic peritoneal endometriosis. This early finding points to a new direction for future research; nevertheless, more studies are required to confirm this and understand how this metabolite balance may be involved in the disease.子宫内膜异位症（Endometriosis）是一种慢性炎症性疾病，育龄女性患病率约为10%。既往研究表明，代谢通路是开发新型治疗策略的潜在方向，亦可用于该病的早期诊断。本研究旨在通过孟德尔随机化（Mendelian randomisation, MR）分析，探究1400种代谢物与不同子宫内膜异位症亚型之间的潜在因果关系。研究分析了全基因组关联研究的数据。MR分析采用逆方差加权法、MR-Egger以及加权中位数法，并辅以异质性检验、敏感性分析与多效性分析。对初步筛选出的差异代谢物开展代谢通路富集分析，随后对经多重检验校正后仍保留因果关联的暴露-结局对进行共定位分析。 经多重检验校正后，仅甘油与棕榈酰肉碱（C16）的比值可降低1~2期子宫内膜异位症的发病风险（经假发现率校正的P值（PFDR）=0.045；比值比（odds ratio, OR）为0.737；95%置信区间（confidence interval, CI）为0.638~0.852）以及盆腔腹膜型子宫内膜异位症的发病风险（PFDR=0.039；OR=0.721；95%CI=0.619~0.841）。共定位分析显示，二者在遗传层面不存在共享的因果变异位点。反向孟德尔随机化分析未发现反向因果关联。代谢通路富集分析鉴定出多条主要代谢通路，包括咖啡因代谢、谷胱甘肽代谢、精氨酸生物合成、鞘脂代谢、泛酸与辅酶A生物合成、缩醛磷脂合成以及不饱和脂肪酸生物合成。 本研究从孟德尔随机化视角揭示了代谢物与不同子宫内膜异位症亚型之间的潜在因果关联。然而，经多重检验校正后仅存少量关联，提示本研究结果尚属初步，需在更大规模队列中予以验证。本探索性分析或有助于推动未来基于代谢组学的子宫内膜异位症诊断、治疗与预防研究。 子宫内膜异位症是指类似子宫内膜的组织在子宫外生长的病症，约影响每10名育龄女性中的1位，可引发疼痛与生育功能障碍。本研究探讨了血液中名为代谢物的特定天然物质是否在不同类型的子宫内膜异位症中发挥作用。本研究利用遗传数据对1000余种代谢物开展检测，发现仅甘油与棕榈酰肉碱的比值存在具有统计学意义的关联。较高的该比值或可降低轻度子宫内膜异位症以及盆腔腹膜型子宫内膜异位症的发病风险。这一早期发现为未来研究指明了新方向，但仍需更多研究加以证实，并阐明该代谢物平衡如何参与疾病发生过程。