Genetically Proxied Antiplatelet Drug Target Perturbation and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Analysis

Abstract

Background: The impact of antiplatelet drugs (APDs) on the rupture risk of unruptured intracranial aneurysms (uIAs) remains controversial. This study aimed to evaluate the causal effects of APDs on aneurysmal subarachnoid hemorrhage (aSAH) and uIA.

Methods: A two-sample Mendelian randomization (TSMR) analysis examined associations between genetically proxied platelet reactivity and aSAH. The therapeutic inhibition of platelet aggregation by 5 widely used APDs was proxied by expression quantitative trait loci from eqtlGen consortium and Genotype-Tissue Expression project v8 consortium and protein quantitative trait loci from deCODE database. Causal effects were estimated with summary-data-based MR, TSMR, colocalization analysis, and sensitivity analysis. Mediation MR analysis explored potential pathways.

Results: The platelet reactivity was inversely associated with the risk of aSAH, exhibiting no discernible heterogeneity or pleiotropic effects (odds ratio, 0.883; 95% confidential interval, 0.833-0.936; P = 2.67E-05). No causal effects on the aSAH and uIA were observed for the majority of APD target genes by summary-data-based MR, TSMR, and colocalization analysis. However, elevated genetic expression of platelet endothelial aggregation receptor 1 was associated with increased platelet reactivity with an odds ratio of 1.46 (β1=0.375, se=0.072; P = 1.99E-07), and this elevation showed significant inverse association with aSAH risks (β2=-0.125, se=0.030; P = 2.67E-05).

Conclusions: The platelet reactivity was inversely associated with aSAH risk. However, APDs were not identified as either risk or protective agents for aSAH or uIA. Targeting platelet endothelial aggregation receptor 1 might reduce platelet reactivity and increase aSAH risk, highlighting the need for further research.

Keywords: Aneurysmal subarachnoid hemorrhage; Antiplatelet drugs; Intracranial aneurysm; Unruptured.