Genetic Insights Into Lipid Traits and Lipid-Modifying Drug Targets in Pregnancy Complications: A Two-Sample Mendelian Randomization Study

Huijing Shao,1,* Chang Xu,2,* Caihong Zhang,2 Lirong Li,3 Pengfei Wu,4 Zixi Chen,5 Rui Guan2 1Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Department of Obstetrics and Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China; 3Department of Traditional Chinese Gynecology, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 4Department of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, 200080, People’s Republic of China; 5Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rui Guan, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Naval Medical University, No. 168 Changhai Road, Yangpu District, Shanghai, 200433, People’s Republic of China, Email [email protected]: Dyslipidemia is linked to pregnancy complications, but its causal role remains uncertain. This two-sample Mendelian Randomization (MR) study investigated the causal relationship between lipid traits and pregnancy complications and evaluated the impact of lipid-modifying drug targets.Methods: Genetic instruments for lipid traits and targets for lipid-modifying drugs were obtained from the Global Lipids Genetics Consortium. Three pregnancy complications’ summary statistics came from the FinnGen R9 database. Significant drug targets underwent further analysis using Expression Quantitative Trait Loci data, and mediation analysis identified potential mediators.Results: Increased high-density lipoprotein cholesterol (HDL-C) reduced the incidence of preeclampsia (OR: 0.755, 95% CI: 0.639– 0.891, p=0.001, FDR=0.012) and gestational diabetes mellitus (GDM) (OR: 0.835, 95% CI: 0.741– 0.942, p=0.003, FDR=0.018). Genetic proxies for cholesteryl ester transfer protein (CETP) inhibition correlated with a decreased risk of preeclampsia (OR: 0.863, 95% CI: 0.786– 0.947, p=0.002, FDR=0.027), while genetic inhibition of HMG-CoA reductase (HMGCR) increased preeclampsia risk (OR: 1.700, 95% CI: 1.189– 2.431, p=0.004, FDR=0.036). Genetically mimicking the enhancement of lipoprotein lipase (LPL) related to a reduced risk of GDM (OR: 0.681, 95% CI: 0.560– 0.829, p=1.29× 10− 4, FDR=0.004). Higher LPL expression in subcutaneous adipose tissue also reduced GDM risk (OR: 0.642, 95% CI: 0.454– 0.909, p=0.013). Waist circumference (4.2%) and waist-to-hip ratio adjusted by BMI (5.7%) partially mediated LPL’s effect on GDM risk.Conclusion: Elevated HDL-C levels help prevent preeclampsia and GDM. CETP and LPL could be therapeutic targets for preeclampsia and GDM, respectively. However, caution is advised with HMGCR-targeting drugs, as they may increase the preeclampsia risk.Keywords: lipids, lipid-modifying drugs, preeclampsia, gestational diabetes mellitus, Mendelian randomization