Abstract
BACKGROUND: Calcific aortic valve stenosis (CAVS), the predominant valvular heart disease in developed countries, arises primarily from metabolic and inflammatory dysregulation. The triglyceride-glucose (TyG) index, a composite biomarker of insulin resistance and systemic inflammation, has been associated with cardiovascular diseases. However, its causal association with CAVS remains unclear. This study employs bidirectional Mendelian randomization (MR) to elucidate the potential causal relationship between the TyG index and CAVS. METHODS: Genome-wide association study) summary statistics of TyG index and CAVS were obtained from UK-biobank cohort (n = 273 368) and FinnGen database (cases = 12 418 and controls = 487 930). Two-sample MR and multiple MR analyses were conducted to evaluate the association of TyG index with CAVS. The primary method was inverse variance weighted (IVW), complemented by MR-Egger, weighted median, and sensitivity analyses to ensure robustness. RESULTS: The MR analysis demonstrated a significant causal effect of the higher TyG index (per 1-unit increment of TyG index) on CAVS risk (odds ratio [OR] = 1.50, P = .007, 95% CI: 1.12-2.02). Similar causal relationships were observed for triglyceride and glucose levels with CAVS. Sensitivity analyses confirmed robustness with no evidence of horizontal pleiotropy (P > .05). This association remained statistically significant in multiple MR analyses after adjusting for potential confounders (OR = 1.64, P = .003, 95% CI: 1.18-2.28). No reverse causality from CAVS to the TyG index was detected. CONCLUSION: This MR study provides evidence supporting the causal effect of higher TyG index on CAVS.