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. 2024 May 31;19(5):e0301752.
doi: 10.1371/journal.pone.0301752. eCollection 2024.

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

Hongling Zhang  1 , Yawei Fan  2 , Huijun Li  3 , Xiaoqing Feng  1 , Daoyuan Yue  3
Affiliations

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

Hongling Zhang et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Overview of research design and analysis strategy.
MR, Mendelian randomization; MVMR, Multivariate MR; UVMR, Univariable MR; DTMR, Drug-target MR; BMI: Body Mass Index; SNP, Single Nucleotide Polymorphism; MR-PRESSO, MR Pleiotropy Residual Sum and Outlier; LDL-C, Low-Density Lipoprotein Cholesterol; HDL-C, High Density Lipoprotein Cholesterol; TG, Triglyceride; IR, Insulin resistance; TC, Total cholesterol; TT, Total Testosterone; SHBG, Sex hormone binding globulin; EUR, European; EAS, East Asian; E2, Oestradiol; DPB, Diastolic blood pressure; SBP, Systolic blood pressure; ANGPTL3, angiopoietin-like 3; FDR, false discovery rate.
Fig 2
Fig 2
Summary of scatterplot results in the discovery dataset (A) HDL-C on EMS-EUR (B) LDL-C on EMS-EUR (C) TG on EMS-EUR (D) TC on EMS-EUR (E) HDL-C on EMS-EAS (F) LDL-C on EMS-EAS (G) TG on EMS-EAS (H) TC on EMS-EAS. LDL-C, Low-Density Lipoprotein Cholesterol; HDL-C, High Density Lipoprotein Cholesterol; TG, Triglyceride; TC, total cholesterol; EMS, endometriosis; EUR, European; EAS, East Asian.
Fig 3
Fig 3. Summary of results of univariable Mendelian randomization.
LDL-C, Low-Density Lipoprotein Cholesterol; HDL-C, High Density Lipoprotein Cholesterol; TG, Triglyceride; FDR, false discovery rate; TC, total cholesterol; EMS, endometriosis; EUR, European; EAS, East Asian.
Fig 4
Fig 4. MR association between TG mediated by gene PPARA, LPL, ANGPTL3 or APOC3 and EMS(EUR).
MR, Mendelian randomization; PPARA, Peroxisome Proliferator-Activated Receptor Alpha; LPL, lipoprotein lipase; ANGPTL3, angiopoietin-like 3; APOC3, Apolipoprotein C-II; TG, triglycerides; EMS, endometriosis; EUR, European.
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The author(s) received no specific funding for this work.