Yan Fei, Chen Zhouxiang, Wu Lingfeng, Huang Zongju
Department of Acpuncture and Moxibustion, Jiangbei District Hospital of Traditional Chinese Medicine, Chongqing, China.
Department of Reproductive Medicine, Hezhou People's Hospital of Guangxi, Hezhou, Guangxi, China.
J Obstet Gynaecol. 2025 Dec;45(1):2552402. doi: 10.1080/01443615.2025.2552402. Epub 2025 Aug 28.
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 ( = 0.045; odds ratio [OR], 0.737; 95% confidence interval [CI], 0.638-0.852) and pelvic peritoneal endometriosis ( = 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.
子宫内膜异位症是一种慢性炎症性疾病，在育龄女性中的患病率约为10%。既往研究已证明代谢途径是开发新治疗策略的潜在途径，且可用于该疾病的早期诊断。本研究旨在使用孟德尔随机化（MR）分析调查1400种代谢物与各种子宫内膜异位症亚型之间的潜在因果关系。
分析了来自全基因组关联研究的数据。使用逆方差加权法、MR-Egger法和加权中位数法进行MR分析，并进行异质性检验、敏感性分析和多效性分析。对初步筛选出的差异代谢物进行代谢途径富集分析，随后对经过多重检验校正后仍存在因果关联的暴露-结局对进行共定位分析。
经过多重检验校正后，只有甘油与棕榈酰肉碱（C16）的比值降低了1-2期子宫内膜异位症的风险（P = 0.045；优势比[OR]，0.737；95%置信区间[CI]，0.638-0.852）以及盆腔腹膜子宫内膜异位症的风险（P = 0.039；OR，0.721；95%CI，0.619-0.841）。共定位分析表明，它们在基因水平上不共享因果变异位点。在反向孟德尔分析中未发现反向因果关联。代谢途径富集分析确定了主要代谢途径，包括咖啡因代谢、谷胱甘肽代谢、精氨酸生物合成、鞘脂代谢、泛酸和辅酶A生物合成、缩醛磷脂合成以及不饱和脂肪酸生物合成。
我们的研究从MR角度提示了代谢物与各种子宫内膜异位症亚型之间的潜在因果关系。然而，经过多重检验校正后幸存的关联数量有限，表明这些发现是初步的，需要在更大的队列中进行验证。这项探索性分析可能有助于推动未来基于代谢组学的子宫内膜异位症诊断、治疗和预防研究。
