Immune cell signatures and preeclampsia: Unveiling causal links through genome-wide association studies

The immune-placental interaction could potentially contribute both causally and therapeutically to preeclampsia (PE). However, previous observational studies have not demonstrated a causal association between these 2 factors. Exploring the causal relationship between immune cells and PE provides genetic evidence that immune cells play a role in PE risk. Using a large dataset of genome-wide association studies, we conducted a bidirectional Mendelian randomization (MR) analysis to determine whether 731 immune cell signatures were correlated with PE, which included 4 types of immune signatures. After false discovery rate (FDR) correction, 3 immunophenotypes were identified to be significantly associated with PE risk: human leukocyte antigen on dendritic cells (odds ratio [OR] = 1.072, 95% confidence interval [CI] = 1.0352-1.110, PFDR = .012), absolute T cell count (OR = 1.477, 95% CI = 1.281-1.703, PFDR = 1.71 × 10-5), and absolute lymphocyte count (OR = 1.514, 95% CI = 1.306-1.755, PFDR = 1.58 × 10-5). Furthermore, PE did not affect immunophenotypes significantly after FDR adjustment, but 12 suggestive immunophenotypes were detected without FDR adjustment, including CD3 on activated and secreting CD4 regulatory T cell (β = 0.467, P = .039), CD3 on CD39 + CD4 + T cell (β = 0.508, P = .024), CD3 on CD45RA + CD4 + T cell (β = 0.515, P = .022), CD3 on CD28 + CD45RA + CD8 + T cell (β = 0.494, P = .028), CD3 on CD39 + CD8 + T cell (β = 0.486, P = .029), CD45 on HLA DR + CD8 + T cell (β = 0.518, P = .018), CD3 on secreting CD4 regulatory T cell (β = 0.508, P = .025), CD25 on resting CD4 regulatory T cell (β = 0.496, P = .018), CD4 on CD39 + activated CD4 regulatory T cell (β = 0.445, P = .048), CD3 on CD28 + CD45RA - CD8 + T cell (β = 0.498, P = .024), CD3 on effector memory CD4 + T cell (β = 0.614, P = .007), and CD3 on activated CD4 regulatory T cell(β = 0.444, P = .049). Using genetic methods, this study uncovers the close relationship between immune cells and PE, which provides guidance for future clinical trials.