Genetic association of serum lipids and lipid-modifying targets with endometriosis: Trans-ethnic Mendelian-randomization and mediation analysis

BACKGROUND: Prior observational research identified dyslipidemia as a risk factor for endometriosis (EMS) but the causal relationship remains unestablished due to inherent study limitations. METHODS: Genome-wide association study data for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from European (EUR) and East Asian (EAS) ancestries were sourced from the Global Lipids Genetics Consortium. Multi-ancestry EMS data came from various datasets. Univariable Mendelian randomization (MR) examined causal links between serum lipids and EMS. Multivariable and mediation MR explored the influence of seven confounding factors and mediators. Drug-target MR investigates the association between lipid-lowering target genes identified in positive results and EMS. The primary method was inverse-variance weighted (IVW), with replication datasets and meta-analyses reinforcing causal associations. Sensitivity analyses included false discovery rate (FDR) correction, causal analysis using summary effect estimates (CAUSE), and colocalization analysis. RESULTS: IVW analysis in EUR ancestry showed a significant causal association between TG and increased EMS risk (OR = 1.112, 95% CI 1.033-1.198, P = 5.03×10-3, PFDR = 0.03), supported by replication and meta-analyses. CAUSE analysis confirmed unbiased results (P < 0.05). Multivariable and mediation MR revealed that systolic blood pressure (Mediation effect: 7.52%, P = 0.02) and total testosterone (Mediation effect: 10.79%, P = 0.01) partly mediated this relationship. No causal links were found between other lipid traits and EMS (P > 0.05 & PFDR > 0.05). In EAS ancestry, no causal relationships with EMS were detected (P > 0.05 & PFDR > 0.05). Drug-target MR indicated suggestive evidence for the influence of ANGPTL3 on EMS mediated through TG (OR = 0.798, 95% CI 0.670-0.951, P = 0.01, PFDR = 0.04, PP.H4 = 0.85%). CONCLUSIONS: This MR study in EUR ancestry indicated an increased EMS risk with higher serum TG levels.