Causal effects of Annexin A1 and Annexin A2 on ischemic stroke and its subtypes: A two-sample Mendelian randomization study.

Background: Preclinical studies have suggested that Annexin A1 and Annexin A2 act as anti-inflammatory agents, slowing the progression of atherosclerosis and further potentially reducing the risk of ischemic stroke. Since the causality of Annexins and ischemic stroke remains uncertain, this study aimed to investigate the causal effects of both using a two-sample Mendelian randomization (MR) method.

Methods: The genetic instruments associated with Annexin A1 and Annexin A2 originated from a European-descent genome-wide association study (GWAS) of 50,000 participants from the INTERVAL study. Summary statistics for ischemic stroke and ischemic stroke subtypes were derived from the MEGASTROKE consortium's GWAS dataset, involving 40,585 cases and 406,111 controls of European ancestry. The inverse-variance weighted method was utilized in the main analysis, followed by a series of sensitivity analyses for robustness validation.

Results: In the primary analysis, genetically predicted high Annexin A1 levels were associated with decreased risks of ischemic stroke (OR = 0.96; 95 % CI = 0.93-0.99; p = 0.023) and large artery stroke (OR = 0.88; 95 % CI = 0.81-0.96; p = 0.004). Similarly, genetically predicted high Annexin A2 levels also had significant associations with decreased risks of ischemic stroke (OR = 0.97; 95 % CI = 0.95-1.00; p = 0.019) and large artery stroke (OR = 0.90; 95 % CI = 0.85-0.96; p = 0.001).

Conclusion: In this two-sample MR study, we found that Annexins had causal protective effects against ischemic stroke, especially large artery stroke. Further basic mechanistic studies should be conducted to investigate the biological roles of these genes.