Stage-Dependent Genetic Association of the TyG Index with Cardiovascular-Kidney-Metabolic Syndrome Severity: A Genome-Wide Association and Mendelian Randomization Study.

We aimed to determine whether the genetically predicted triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is associated with cardiovascular-kidney-metabolic (CKM) stage severity and whether these associations are consistent with a potential causal role of insulin resistance within the CKM staging framework. The associations between the TyG index and CKM stages were assessed among 107,161 Taiwan Biobank participants using multivariable regression. CKM stages 3 and 4 were combined as the advanced CKM stage group. A genome-wide association study (GWAS) in 104,778 participants identified genetic determinants of the TyG index, followed by Mendelian randomization (MR), weighted genetic risk score (wGRS) analyses, and sample-split MR analyses. CKM stage severity was evaluated using ordinal regression analysis, a sensitivity analysis (CKM stages ≥ 1 vs. stage 0), and a later-stage comparison analysis (CKM stages ≥ 2 vs. stages 0-1). The TyG index increased progressively across CKM stages. GWAS identified 61 genome-wide significant loci associated with the TyG index. MR analyses demonstrated that genetically predicted TyG index was associated with greater CKM stage severity across all models, with consistent findings in the sample-split analyses. Genetic associations were modest for CKM stage 1 versus stage 0 but became substantially stronger for CKM stage 2 and the advanced CKM stages. Genetically predicted TyG index was associated with higher CKM stage severity in a stage-dependent manner, with substantially stronger genetic associations from CKM stage 2 onward. These findings are consistent with a potential causal role of insulin resistance in CKM stage severity and highlight the TyG index as a complementary biomarker for metabolic risk stratification.