Associations between novel triglyceride glucose and adiposity-related indices and risk of metabolic dysfunction-associated steatotic liver disease: the mediating role of biological aging and evidence from the UK Biobank

Abstract

Background Insulin resistance (IR) plays a critical role in the development and prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, evidence regarding associations between novel triglyceride glucose (TyG) and adiposity-related composite indices, serving as simple IR surrogates, and the risk of incident MASLD remains limited. This study aimed to evaluate associations between six novel TyG-related composite indices and MASLD risk, as well as the potential mediating role of biological aging. Methods This prospective cohort study included 426,831 participants from the UK Biobank, who were free of MASLD at baseline. Six novel TyG and adiposity-related composite indices [e.g., TyG-body mass index (BMI), TyG-waist circumference (WC), TyG-waist-to-height ratio (WHtR), TyG-body roundness index (BRI), TyG-a body shape index (ABSI), and TyG-weight-adjusted-waist index (WWI)] were calculated. Kaplan-Meier curves, Cox proportional hazards models, and restricted cubic splines (RCS) analyses were applied to evaluate associations between novel TyG-related indices and MASLD risk. Predictive performance was evaluated using Harrell’s C-index, net reclassification index (NRI), and integrated discrimination improvement index (IDI). Mediation analyses were performed to explore the potential role of biological aging. Additionally, MRI-measured proton density fat fraction (PDFF) was used to defined MASLD and investigate its association with TyG-related indices. Results Over a median follow-up of 13.72 years, 6,308 new-onset MASLD cases were recorded. All six TyG-related composite indices were significantly associated with an increased risk of incident MASLD. Compared with the lowest quartile, hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest quartile were 6.28 (5.62-7.02) for TyG-BMI, 8.27 (7.34-9.30) for TyG-WC, 8.18 (7.24-9.23) for TyG-WHtR, 7.79 (6.91-8.78) for TyG-BRI, 3.86 (3.49-4.26) for TyG-ABSI, and 6.06 (5.42-6.78) for TyG-WWI. RCS analyses revealed nonlinear relationships of all TyG-related indices and MASLD risk (all P for non-linearity <0.001). Incorporating novel TyG-related indices significantly improved predictive performance, with the greatest gains observed for TyG-WHtR and TyG-WC. Mediation analyses indicated that biological aging, assessed by KDM-BA and PhenoAge, accounted for 3%-12% of these associations. Results were consistent across subgroup and sensitivity analyses and when MASLD was defined as PDFF ≥5%. Conclusion Six novel TyG and adiposity-related composite indices were independently associated with the risk of incident MASLD. These indices, particularly TyG-WHtR and TyG-WC, may server as simple and effective predictors for MASLD. Biological aging partially mediated these associations, offering novel insights into the pathways from IR to MASLD development.