Gene associations of lipid traits, lipid-lowering drug-target genes and endometriosis

Abstract

Research Question

Does the observed correlation between dyslipidemia and endometriosis indicate bidirectional causal associations? Furthermore, is the prospect of utilizing lipid-lowering drugs to manage endometriosis a viable strategy?

Design

Bidirectional Mendelian Randomization (MR) is employed to investigate the causal association between lipid traits and endometriosis. Drug-target MR is utilized to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets are significant, aggregate analyses, such as Summary-data-based Mendelian Randomization (SMR) and Colocalization methods, are introduced to validate the outcomes. Mediation analyses supplement these evaluations.

Results

Bidirectional MR results suggested that genetically predicted triglycerides (TG) (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.08-1.23), high-density lipoprotein cholesterol (HDL-C) (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (LDL-C) (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (APOA) (OR 0.90, 95% CI 0.83-0.96) were causally associated with endometriosis. Reverse MR results revealed that genetically proxied endometriosis was causally associated with TG level (OR 1.02, 95% CI 1.01-1.02). In drug-target MR, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR1.40, 95% CI 1.13-1.72), apolipoprotein B (APOB) (OR 1.49, 95% CI 1.21-1.86) and Angiopoietin-related protein 3 (ANGPTL3) (OR 1.57, 95% CI 1.14-2.16) were significantly associated with the risk of endometriosis stages 1-2.

Conclusion

Our findings suggest a potential bidirectional causal association between endometriosis and dyslipidemia. Genetic mimicry of PCSK9, APOB, and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs for treating endometriosis holds potential clinical interest.