Triglyceride-glucose index, plasma metabolome and aortic stenosis: a Mendelian randomization analysis

The association between the Triglyceride-Glucose index, an emerging marker of insulin resistance, and the risk of aortic stenosis remains unclear. The influence of Triglyceride-Glucose index on aortic stenosis may be mediated through plasma metabolites. To investigate the potential causal relationships between the Triglyceride-Glucose index, plasma metabolites, and aortic stenosis, we employed a two-sample Mendelian randomization approach. We conducted univariable Mendelian randomization analyses to explore the associations between (i) the Triglyceride-Glucose index and aortic stenosis; (ii) plasma metabolites and aortic stenosis; and (iii) the Triglyceride-Glucose index and plasma metabolites. For significant associations identified through Mendelian randomization, a two-step MR analysis was employed to evaluate mediation effects. The genetically predicted Triglyceride-Glucose index is positively associated with aortic stenosis (OR 1.74, 95% confidence interval 1.41, 2.16). Following adjustments for multiple testing, there were 15 notable associations between genetically predicted metabolites and aortic stenosis. Additional analyses estimated the indirect effects of the TyG index on AS through these metabolites. Notably, the mediation effect of various metabolites was quantified: 1-arachidonoyl-gpc (20:4n6) exhibited a mediation effect of 0.06 (95% CI: 0.02 to 0.11, P = 4.38E-03); 1-stearoyl-2-arachidonoyl-gpc (18:0/20:4) had a mediation effect of 0.08 (95% CI: 0.03 to 0.12, P = 6.60E-04); 1-stearoyl-2-arachidonoyl-gpe (18:0/20:4) showed an effect of 0.12 (95% CI: 0.06 to 0.17, P = 6.58E-05); 1-palmitoyl-2-arachidonoyl-gpe (16:0/20:4) demonstrated a mediation effect of 0.07 (95% CI: 0.03 to 0.11, P = 8.75E-04); 1-palmitoyl-2-docosahexaenoyl-gpe (16:0/22:6) showed an effect of 0.09 (95% CI: 0.03 to 0.14, P = 1.26E-03); and 1-oleoyl-2-arachidonoyl-gpe (18:1/20:4) had an effect of 0.08 (95% CI: 0.03 to 0.13, P = 5.38E-04). The genetically predicted Triglyceride-Glucose index is positively associated with the risk of aortic stenosis, and this relationship is partially mediated by specific metabolites.