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

Ge Zhou; Jin Ren; Qiuyan Huang; Xiaowei Nie; Xingli Tong; Ya Wen Cui; Rongkui Hu; Qi Yao

doi:10.1016/j.rbmo.2024.103856

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

Reprod Biomed Online. 2024 Feb 2;49(1):103856. doi: 10.1016/j.rbmo.2024.103856. Online ahead of print.

Authors

Ge Zhou¹, Jin Ren², Qiuyan Huang², Xiaowei Nie¹, Xingli Tong¹, Ya Wen Cui², Rongkui Hu³, Qi Yao⁴

Affiliations

¹ Department of Reproductive Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China.
² Department of Reproductive Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; The First College of Clinical Medical, Nanjing University of Chinese Medicine, Nanjing, China.
³ Gynaecology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China. Electronic address: fsyy00637@njucm.edu.cn.
⁴ Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China. Electronic address: qiqiyao@126.com.

PMID: 38657291
DOI: 10.1016/j.rbmo.2024.103856

Abstract

Research question: Does the observed correlation between dyslipidaemia and endometriosis indicate a bidirectional causal association?

Design: Bidirectional Mendelian randomization was used to investigate the causal association between lipid traits and endometriosis. Drug-target Mendelian randomization was used to explore potential drug-target genes for managing endometriosis. In cases where lipid-mediated effects via specific drug targets were significant, aggregate analyses, such as summary-data-based Mendelian randomization and colocalization methods, were introduced to validate the outcomes. Mediation analyses supplemented these evaluations.

Results: The bidirectional Mendelian randomization results suggested that genetically predicted triglyceride (OR 1.15, 95% CI 1.08-1.23), high-density lipoprotein cholesterol (OR 0.87, 95% CI 0.81-0.94), low-density lipoprotein cholesterol (OR 1.20, 95% CI 1.06-1.34) and apolipoprotein A (OR 0.90, 95% CI 0.83-0.96) concentrations were causally associated with endometriosis. Reverse Mendelian randomization results revealed that genetically proxied endometriosis was causally associated with triglyceride concentration (OR 1.02, 95% CI 1.01-1.02). In drug-target Mendelian randomization, genetic mimicry in proprotein convertase subtilisin/kexin type 9 (PCSK9) (OR 1.40, 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) was significantly associated with the risk of endometriosis stages 1-2.

Conclusion: There is a potential bidirectional causal association between endometriosis and dyslipidaemia. Genetic mimicry of PCSK9, APOB and ANGPTL3 is associated with the risk of early-stage endometriosis. The development of lipid-lowering drugs to treat endometriosis is of potential clinical interest.

Keywords: Dyslipidaemia; Endometriosis; Mendelian randomization; Target gene.