Abstract MP50: Effect of Linoleic Acid on Ischemic Stroke: A Mendelian Randomization Study

Abstract

Background and Purpose: Linoleic acid (LA) is an essential fatty acid involved in eicosanoid synthesis. Epidemiological studies have suggested an inverse association between circulating LA levels and ischemic stroke (IS), however, it is unclear whether the observed association is causal or due to confounding or reverse causation. We conducted a Mendelian randomization (MR) to evaluate the potential causal relationship between circulating LA levels and risk of IS. Methods: Summary statistics for IS were obtained from the MEGASTROKE consortium, including 34,217 IS cases and 404,630 controls of European ancestry. Seventeen single nucleotide polymorphisms (SNPs) associated with circulating LA levels were used as instrumental variables (IVs) in the MR analysis, with another two SNP sets used in sensitivity analyses. We used the inverse-variance weighted method to evaluate the potential causal associations of circulating LA levels with IS, complemented with other MR approaches including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression. Results: Each 1-standard deviation increase of genetically-predicted LA levels was inversely associated with a 2% (95% confidence interval [CI], 1%-3%) reduction in IS incidence. Subgroup analyses showed significant causal associations for large artery stroke (OR, 0.95; 95% CI, 0.92-0.98; P =3.45х10 -4 ), but not for cardioembolic stroke (OR, 0.98; 95% CI, 0.96-1.00; P =0.05) and small vessel stroke (OR, 1.02; 95% CI, 0.99-1.05; P =0.11). Sensitivity analyses using two additional SNP sets as IVs produced consistent findings. Conclusions: Our study provides evidence for an inverse causal association of circulating LA levels with risk of IS, particularly large artery stroke. Further studies are warranted to clarify the underlying mechanism of LA in the prevention of IS.