ZDHHC13 Reduces the Risk of Ischemic Stroke by Regulating Metabolites

Recent studies have shown that palmitoylation is involved in ischemic stroke(IS). However, the role of palmitoylation in IS has not been systematically investigated. The aim of this study is to explore the causal relationship and mechanism between palmitoylation genes, metabolites, and IS using Mendelian randomization (MR) method. The GWAS data of IS from GISCOME network database, the palmitoylation gene data from eQTLGen database, and the metabolite data from GWAS database were used in this study. Two-sample MR analysis, summary-based Mendelian randomization (SMR) analysis, and mediation analysis were used. Firstly, two-sample MR analysis was used to evaluate the causal relationship between palmitoylation genes and IS. The SMR method was then used to verify the correlation between gene expression and IS. The GSE140275 dataset of GEO database was used to test the expression of palmitoylation genes. Mediation analysis was used to explore the mediating effect between palmitoylation gene expression and metabolites and IS (metabolites are mediators, genes are exposures). The high expression of ZDHHC13 gene is significantly negatively correlated with the risk of IS. ZDHHC13 indirectly affects the occurrence of IS by regulating Mannonate metabolites. Sensitivity and SMR analyses supported our findings, indicating high statistical robustness. Based on the observational results serum data set of IS patients, the expression of ZDHHC13 is decreased after IS. However, ZDHHC13 has a protective effect before the occurrence of ischemic stroke, which MR analysis result is contrary to observational results. This study reveals the role of ZDHHC13 in the progression of IS by regulating Mannonate metabolites and provides potential clinical application prospects for ZDHHC13 as a biomarker or preventive target for early diagnosis and treatment of IS.