Causal relationship between liver enzymes and stroke:a two-sample Mendelian randomization study

Wang Enzhong; Lu Yan

doi:10.3969/j.issn.1002-1949.2024.05.009

Abstract：Objective To investigate the potential causal relationship between genetically predicted liver enzyme levels[aspartate aminotransferase(AST),alanine aminotransferase(ALT)and gamma-glutamyl transpeptidase(GGT)]and stroke[ischemic stroke(IS)and intracerebral hemorrhage(ICH)].Methods A two-sample Mendelian randomization(MR)design was used to evaluate the causal effects of three liver enzymes on stroke risk based on large-scale genome-wide association study(GWAS)pooled data.The causal relationship between liver enzymes and stroke risk was simultaneously investigated by univariate MR and multivariate MR.Inverse variance weighted(IVW)method was used as the main MR analysis method,and MR-Egger,weighted median method,weighted mode and MR-PRESSO were ultilized as supplementary analysis methods.Sensitivity analysis was also performed to ensure the robustness of the results.Results The univariate MR showed gene-predicted ALT[OR 1.18,95%CI 1.08-1.28,P = 9.39×10-5]and GGT(OR =1.11,95%CI 1.05-1.17,P =1.08×10-4)levels were significantly positively associated with IS risk,but no causal relationship was found between AST(OR =1.08,95%CI 1.00-1.18,P =0.060)and IS risk.Furthermore,ALT(OR = 1.09,95%CI 0.83-1.44,P =0.536),GGT(OR =0.92,95%CI 0.79-1.08,P =0.323)and AST(OR =1.23,95%CI 0.99-1.52,P =0.067)were not causally associated with the CIH risk.Multivariate MR showed that after adjusting for gender,low-density lipoprotein cholesterol(LDL-C),smoking,drinking,body mass index(BMI)and other risk factors,the higher ALT and GGT levels remained significantly associated with increased IS risk.However,a causal relationship between GGT levels and IS risk did not emerge in the multivariate MR analysis after adjusting for these risk factors simultaneously.Conclusions There is a potential positive causal relationship of genetically predicted GGT and ALT with IS.These findings may provide important information for prevention strategies and interventions targeting liver enzyme levels and IS risk.