Causal and mediating link between sarcopenia and nonalcoholic fatty liver disease: A bidirectional two-sample, two-step Mendelian randomization study.

BACKGROUND AND AIM

Recent research underscores potential links between sarcopenia traits and nonalcoholic fatty liver disease (NAFLD), but the causal mechanisms and pathways mediating these links are not yet clear. The objective of this research is to tackle this problem through a bidirectional two-step Mendelian randomization (MR) study.

METHODS AND RESULTS

We applied a bidirectional MR approach to large-scale European genomic datasets to examine the causal relationships between sarcopenia traits-appendicular lean mass (ALM), handgrip strength, and walking pace (WP)-and NAFLD risk. Instrumental variables were derived from genome-wide association studies, with detailed mediation analyses encompassing 19 metabolic and inflammatory biomarkers. Our findings indicated that a genetically higher ALM (OR = 0.918, 95 % CI: 0.847-0.994, P = 0.036) and quicker WP (OR = 0.435, 95 % CI: 0.240-0.789, P = 0.006) were unidirectionally protective against NAFLD. Key mediators in the ALM-NAFLD pathway included waist circumference (WC, -51.10 % mediation effect), waist-to-hip ratio (WHR, 29.32 %), fasting insulin (FI, 51.56 %), high-density lipoprotein cholesterol (HDL-C, -6.81 %), and triglycerides (TG, 5.74 %). For the WP-NAFLD association, significant mediators were body mass index (BMI, 41.61 %), WC (56.43 %), WHR (48.09 %), HDL-C (13.00 %), and TG (6.35 %). Inflammatory biomarkers showed negligible mediation effects, and sensitivity analyses confirmed the robustness of our findings.

CONCLUSIONS

This study provided genetic evidence supporting a unidirectional causal relationship, wherein higher ALM and WP were inversely associated with NAFLD incidence, without evidence of a bidirectional causal link. This relationship was primarily mediated by anthropometric, glycemic, and lipid traits. Interventions targeting these mediators may help reduce the risk of NAFLD in individuals with sarcopenia.