Background: Previous studies have reported associations between fatty acids and the risk of pre-eclampsia. However, the causality of these associations remains uncertain. This study postulates a causal relationship between specific plasma fatty acids and pre-eclampsia or other maternal hypertensive disorders (PE-HTPs). To test this hypothesis, two-sample bidirectional Mendelian randomization (MR) analyses were employed to determine the causality effects. Methods: Single-nucleotide polymorphisms associated with PE-HTPs and fatty acids were obtained from a genome-wide association study (GWAS) of European ancestry. Bidirectional MR analyses were conducted using methods such as inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses, including tests for heterogeneity, horizontal pleiotropy, and co-localization, were conducted to assess the robustness of MR results. Results: The analyses revealed causal relationships between PE-HTPs and several fatty acids, including monounsaturated fatty acid (MUFA), omega-6 fatty acid (n-6 FA), linoleic acid (LA), docosahexaenoic acid (DHA), and the PUFA/MUFA ratio. Genetically predicted higher risk of PE-HTPs was significantly associated with lower plasma n-6 FA (OR = 0.96, 95% CI: 0.93–0.99), particularly LA (OR = 0.95, 95% CI: 0.92–0.98). Conversely, increased DHA (OR = 0.86, 95% CI: 0.78–0.96) and a higher PUFA/MUFA ratio (OR = 0.86, 95% CI: 0.76–0.98) were associated with a reduced risk of PE-HTPs. Elevated MUFA levels (OR = 1.12, 95% CI: 1.00–1.25) were related to an increased risk. Conclusions: This study provides robust genetic evidence supporting bidirectional causal relationships between PE-HTPs and specific plasma fatty acids, underscoring the critical role of fatty acid metabolism in maternal hypertensive disorders.

Background: The impact of dietary fat on dementia risk remains controversial due to conflicting findings on fat subtypes, over-reliance on linear models, and limited attention to fat source balance. Methods: In a large prospective analysis of 97,765 UK Biobank adults, we examined associations between dietary fat composition and incident dementia, integrating genetic susceptibility and metabolomic profiling. Results: Total fat intake, animal fat, and plant fat all showed significant U-shaped associations with dementia risk. Notably, the animal-to-plant fat ratio exhibited a clear U-shaped association ( P _FDR for nonlinearity = 0.011), with the lowest risk observed at a ratio of 0.9. A significant interaction with APOE -ε4 carriage was identified ( P for interaction = 0.041), in which carriers in the lowest quartile of the fat ratio had the highest dementia risk (HR = 3.88, 95% CI: 3.00–5.00). A similar nonlinear pattern was observed for executive function. Mediation analyses implicated very-low-density lipoprotein-related metabolites as key intermediates. Conclusions: These findings highlight the importance of balanced fat sources and support precision nutrition strategies tailored to genetic risk.