Abstract Body: Introduction: Sleep apnea is increasingly recognized as a significant risk factor for preeclampsia/eclampsia (PE). Research increasingly shows that large high-density lipoprotein (L-HDL) may influence the PE development. This study aimed to investigate the association between sleep apnea and PE and the proportion of this association that is mediated through different L-HDL components.
Hypothesis: Modifications in the L-HDL components induced by sleep apnea significantly contribute to the pathogenesis of PE.
Methods: A two-sample Mendelian randomization (MR) was conducted using genetic variants associated with relative sleep apnea from the FinnGen study and different L-HDL components from UK Biobank. The single-nucleotide polymorphisms (SNPs) were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. Then the multivariable MR analysis was performed to estimate the effect of the mediators on the risk of PE with adjustment for sleep apnea. The MR-Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) were mainly used for sensitivity analyses. In mediation analyses, the direct effect of different L-HDL components estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis.
Results: This study found that sleep apnea significantly affects the risk of PE, as well as various L-HDL components, including large high-density lipoprotein cholesterol (L-HDL-C), large high-density lipoprotein cholesteryl ester (L-HDL-CE), large high-density lipoprotein concentration (L-HDL concentration), cholesterol to total lipids ratio in large high-density lipoprotein (C/TL-L-HDL), cholesteryl esters to total lipids ratio in large high-density lipoprotein (CE/TL-L-HDL), and phospholipids to total lipids ratio in large high-density lipoprotein (P/TL-L-HDL). In multivariable MR analysis, these components were also significantly associated with the risk of PE. Additionally, mediation analysis identified P/TL-L-HDL as the only significant mediator between sleep apnea and PE (mediation effect = 0.0224; 95% CI=0.0005, 0.0443; p-value=0.0455).
Conclusion: This study establishes a causal link between sleep apnea and an increased risk of preeclampsia/eclampsia, mediated by P/TL-L-HDL.
Key Words: Sleep apnea; Preeclampsia; Eclampsia; Large HDL; Mendelian randomization; Mediation analysis