GAMMA-GLUTAMYLTRANSFERASE AS A POTENTIAL CONTRIBUTOR TO THE PATHOGENESIS OF ISCHEMIC STROKE: EVIDENCE FROM MENDELIAN RANDOMIZATION AND COLOCALIZATION

In recent years, the independent role of Gamma-Glutamyltransferase (GGT) in ischemic stroke has attracted growing interest, though its causal relationship with ischemic stroke and its subtypes remains uncertain due to limitations in statistical power and confounding. To address this, a Mendelian randomization study was conducted to evaluate the causal association between four liver function markers and ischemic stroke. Additional analyses—including LDSC, co-localization, and GO/KEGG enrichment—were performed to examine genetic correlations, shared causal variants, and underlying biological pathways. Genetically predicted GGT was found to play an independent role in the development of ischemic stroke (OR 1.13; 95% CI 1.06–1.21, P = 0.0004) and showed potential influence across subtypes: large artery atherosclerotic stroke (LAS, OR 1.19; 95% CI 1.01–1.40, P = 0.0398), small vessel stroke (SVS, OR 1.18; 95% CI 1.02–1.37, P = 0.0262), and cardioembolic stroke (CES, OR 1.19; 95% CI 1.06–1.34, P = 0.0041). In contrast, there was insufficient evidence to support a causal effect of genetically predicted ALT, AST, or ALP on ischemic stroke. Co-localization analysis identified two distinct variants, rs2017188 and rs737128, shared between GGT and ischemic stroke (PP4 = 0.8360). GO/KEGG enrichment analysis revealed pathway enrichment related to actin cytoskeleton regulation, platelet activation, and vascular smooth muscle contraction. These findings support a causal relationship between genetically predicted GGT and ischemic stroke, suggesting GGT1 as a potential intervention target for the condition.