Exploring the causal role of fatty acids in ischemic stroke: Insights from Mendelian randomization and inflammatory...

Ischemic stroke (IS) is a leading cause of mortality and disability worldwide, with complex multifactorial pathogenesis. Emerging evidence suggests fatty acids (FAs) and their composition ratios play a crucial role in IS risk and prognosis. However, previous studies have been limited by observational designs. This study sought to determine the causal links between FAs and IS through Mendelian randomization (MR).

We utilized large-scale genome-wide association study (GWAS) data from European populations to evaluate the causal effects of FA types and their composition ratios on IS and its subtypes. MR techniques, including inverse variance weighted (IVW), were employed. Validation cohorts and two-step MR analysis were utilized to further confirm our findings and investigate potential inflammatory mediators. Sensitivity analyses were conducted to ensure robust findings.

Higher linoleic acid (LA)/total FA ratios were associated with reduced IS risk, mediated by increased stem cell factor (SCF) levels, suggesting a protective mechanism involving inflammatory modulation and vascular repair. Specific FA ratios, such as DHA/total FA and PUFA/MUFA, significantly influenced IS risk and recovery outcomes. While DHA/total FA increased IS risk, it was linked to improved post-stroke recovery. Sensitivity analyses confirmed the stability and reliability of these results.

This study offers compelling evidence connecting FA composition ratios to both the risk of IS and recovery outcomes. The findings highlight the dual roles of DHA and the protective effects of LA/total FA via SCF regulation, offering insights for targeted preventive and therapeutic strategies. Further studies are warranted to validate these results in diverse populations.