Investigating the causal role of immune cells in preeclampsia: Insights from Mendelian randomization analysis

Immune-related inflammation is linked to preeclampsia (PE), but immune cell-PE associations remain inconsistent. This study used two-sample Mendelian randomization (MR) to explore causal links between immune cell profiles and PE, informing clinical research and interventions. Genome-wide association study data included 731 immune cell phenotypes (3757 Europeans) and PE (2355 cases/264,887 controls, European descent). Single nucleotide polymorphisms were selected as instrumental variables (IVs) after quality control. Multiple MR methods (inverse variance weighted, weighted median estimator, weighted mode, and MR-Egger) and sensitivity analyses (heterogeneity, leave-one-out, and pleiotropy) were applied; false discovery rate (FDR) correction adjusted for multiple comparisons. Bidirectional MR explored reverse causality. After FDR correction (P_FDR < 0.20), 6 immunophenotypes showed significant causal associations with PE: 3 protective (CD62L-CD86+ myeloid dendritic cell [DC], CD62L- myeloid DC, granulocyte SSC-A levels) and 3 risk-increasing (CD16 on CD14+CD16+ monocytes, human leukocyte antigens DR+ natural killer cells, programmed death-ligand 1 on CD14-CD16+ monocytes). No horizontal pleiotropy was detected, and results were robust. Reverse MR identified 18 suggestive immunophenotypes (P < 5 × 10-6) potentially affected by PE (predominantly B cells) but no reverse causality for the 6 key phenotypes. Six immune cell phenotypes have causal links to PE, highlighting monocytes, myeloid DCs, natural killer cells, and granulocytes in PE pathogenesis. These findings offer potential immune biomarkers and therapeutic targets, emphasizing the need for translational research to validate clinical utility.