Causal effect of lipoprotein-associated phospholipase A2 activity on ischemic stroke : a Mendelian randomization study

Background: The causality between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and ischemic stroke remains uncertain and the stratified research on the association between Lp-PLA2 activity and subtypesof ischemic stroke is still lacking. Therefore, the association of genetically proxied Lp-PLA2 activity with the risks of ischemic stroke and its subtypes was explored by Mendelian randomization in this study. Methods Five single-nucleotide polymorphisms associated with Lp-PLA2 activity were selected as instrumental variables based on the data from CHARGE Consortium with 13,664 European participants. Summary statistics data about MEGESTROKE consortium with the European group (40,585 cases and 406,111 controls) include any ischemic stroke (AIS) (n = 34,217); large-artery stroke (LAS, n=4,373), cardioembolic stroke (CES, n=7,193) and small vessel stroke (SVS, n=5,386). The inverse variance weighted (IVW) method was used as the main analysis to assess the causal associations of Lp-PLA2 activity with ischemic stroke and its subtypes, and significant estimates were further tested by sensitivity analysis to exclude heterogeneity and pleiotropy. Results IVW showed genetically proxied Lp-PLA2 activity was causally associated with LAS (OR=3.25, 95% CI=1.65-6.41, p =0.0007), but not causally associated with AIS (OR=1.32, 95% CI=0.81-2.15, p =0.25), CES (OR=1.18, 95% CI=0.62-2.23, p =0.61) or SVS (OR=1.31, 95% CI=0.73-2.37, p =0.37). Sensitivity analysis for causal estimates between Lp-PLA2 activity and LAS showed no significant heterogeneity or pleiotropy. Conclusions These MR analyses support a causal role of Lp-PLA2 activity in LAS but not in AIS, CES or SVS, which suggests that serum Lp-PLA2 activity might be a biomarker for prediction of LAS.