Mendelian Randomization Mediation Analysis Reveals the Impact of Dietary Preferences on Preeclampsia and Fetal Growth Restriction via Immune Modulation

Preeclampsia (PE) and fetal growth restriction (FGR) are major causes of maternal and neonatal complications. Emerging evidence suggests that dietary preferences may influence their development, but the mechanisms, especially involving immune cells, are not well understood. We performed a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data for dietary preferences, PE, and FGR, sourced from the GWAS Catalog (<i>n</i> = 159,579) and FinnGen (<i>n</i> = 242,332 for PE; <i>n</i> = 254,618 for FGR). Genetic instruments for 731 immune cell traits were extracted from the IEU GWAS database. The primary analysis employed the inverse-variance weighted (IVW) method, with sensitivity analyses (Cochran's <i>Q</i> test, MR-Egger intercept, and MR-PRESSO) to assess heterogeneity and pleiotropy. Reverse MR was performed to investigate potential bidirectional causality. We identified 21 dietary preferences significantly associated with PE risk and 11 with FGR risk. Notably, a preference for chili peppers was linked to a lower risk of PE (OR = 0.762, 95% CI: [0.649, 0.895], <i>p</i> = 0.001), while a preference for hard cheese was associated with a decreased risk of FGR (OR = 0.337, 95% CI: [0.176, 0.646], <i>p</i> = 0.001). Immune cell trait analysis revealed that elevated HLA-DR expression on HLA-DR⁺ CD8⁺ T cells was positively associated with PE risk (OR = 1.068, 95% CI: [1.013, 1.126], <i>p</i> = 0.015), whereas higher levels of IgD⁺ CD24⁺ B cells were inversely associated with FGR risk (OR = 0.883, 95% CI: [0.813, 0.960], <i>p</i> = 0.003). Mediation analysis indicated that 10.9% of the chili pepper's protective effect on PE was mediated by HLA-DR⁺ CD8⁺ T cells (<i>p</i> = 0.042), and 13.9% of the protective effect of hard cheese on FGR was mediated by IgD⁺ CD24⁺ B cells (<i>p</i> = 0.043). Reverse MR analyses provided no evidence of reverse causality. Specific dietary preferences-such as the consumption of chili peppers and hard cheese-may reduce the risk of PE and FGR through immune modulation. These findings highlight the potential of targeted dietary interventions during pregnancy to prevent adverse outcomes and warrant further validation in prospective studies.