Genetically Predicted Causal Risk Factors for Preeclampsia: A Comprehensive Mendelian Randomization Study.

Background: Preeclampsia is a complex hypertensive disorder of pregnancy, significantly impacting maternal and fetal health worldwide. Despite extensive research, its pathogenesis, involving inflammatory, immune, microbiological, and metabolic factors, requires comprehensive elucidation. Methods: This study applied Mendelian randomization (MR) to investigate causal relationships between multi-omics traits and the risk of preeclampsia. The genome-wide association studies (GWAS) datasets used consisted of immune cells (N = 3757), inflammatory factors (N = 14,824), gut microbiota (N = 7738), circulating metabolites (N1 = 7824, N2 = 8299), plasma proteins (N = 3301), and preeclampsia (7212 cases, 194,266 controls). The inverse variance-weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. Results: Our analysis identified 81 potential causal factors for preeclampsia. Among the most novel and clinically significant findings were several druggable plasma proteins, including Astacin-like metalloendopeptidase (ASTL) and Baculoviral IAP repeat-containing protein 3 (BIRC3), which exhibited strong causal evidence. Furthermore, we identified specific gut microbiota genera, notably Bifidobacterium, as potential protective factors. We also validated the causal roles of key metabolic disturbances, like cysteine and guanidinoacetate, and dysfunctions in specific immune cell populations, particularly regulatory T and B cells. Conclusion: These findings highlight the intricate interplay of immune, inflammatory, microbiological, metabolic, and protein factors in preeclampsia, suggesting novel diagnostic and therapeutic targets. Further research is warranted to explore these associations in detail.