Bidirectional Mendelian Randomization Analysis of Genetic Proxies of Plasma Fatty Acids and Pre-Eclampsia Risk

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.

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.

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.

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.