Association of triglyceride glucose index with stroke: from two large cohort studies and Mendelian randomization analysis

Introduction:The triglyceride glucose index (TyG) is associated with cardiovascular diseases; however, its association with stroke remains unclear. This study aimed to elucidate this relationship by examining two extensive cohort studies using two-sample Mendelian randomization (MR).Methods:Using data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) and the Medical Information Mart for Intensive Care (MIMIC)-IV, the correlation between TyG (continuous and quartile) and stroke was examined using multivariate Cox regression models and sensitivity analyses. Two-sample MR was employed to establish causality between TyG and stroke using the inverse variance weighting method. Genome-wide association study catalog queries were performed for single nucleotide polymorphism-mapped genes, and the STRING platform used to assess protein interactions. Functional annotation and enrichment analyses were also conducted.Results:From the NHANES and MIMIC-IV cohorts, we included 740 and 589 participants with stroke, respectively. After adjusting for covariates, TyG was linearly associated with the risk of stroke death (NHANES: hazard ratio [HR] 0.64, 95% CI: 0.41-0.99, P=0.047; Q3 vs. Q1, HR 0.62, 95% CI: 0.40-0.96, P=0.033; MIMIC-IV: HR 0.46, 95% CI: 0.27-0.80, P=0.006; Q3 vs. Q1, HR 0.32, 95% CI: 0.12-0.86; Q4 vs. Q1, HR 0.30, 95% CI: 0.10-0.89, P=0.030, P for trend=0.017). Two-sample MR analysis showed genetic prediction supported a causal association between a higher TyG and a reduced risk of stroke (odds ratio 0.711, 95% CI: 0.641-0.788, P=7.64e-11).Conclusions:TyG was causally associated with a reduced risk of stroke. TyG is a critical factor for stroke risk management.