Association between chitinase 3-like protein 1 and severe non-alcoholic fatty liver disease: a large prospective cohort study in UK Biobank

Introduction: Chitinase-3-like protein 1 (CHI3L1) is a glycoprotein involved in inflammation and fibrosis, but its association with non-alcoholic fatty liver disease (NAFLD) remains unclear. The present study investigated the association between serum CHI3L1 levels and the risk of severe NAFLD in a large prospective cohort. Methods: A prospective cohort study was conducted using UK Biobank data from 50,334 participants. Serum CHI3L1 levels were measured at baseline. Severe NAFLD cases were identified using hospital records. Cox proportional hazards models evaluated the association between CHI3L1 levels and severe NAFLD risk. Restricted cubic spline (RCS) analysis assessed potential non-linearity. Subgroup and mediation analyses were conducted to explore effect modifiers and underlying pathways. Results: Over a median follow-up of 16 years, 766 severe NAFLD cases were identified. Higher CHI3L1 levels were significantly associated with increased severe NAFLD risk (HR = 1.45, 95% CI: 1.34–1.58, P < 0.001). RCS analysis revealed a linear positive association without evidence of non-linearity. Stratified analyses showed consistent associations across subgroups, with no significant interactions. Mediation analysis identified HDL and ALT as partial mediators, explaining 6.38% and 2.86% of the total effect, respectively, while the direct effect of CHI3L1 remained dominant. Discussion: Elevated CHI3L1 levels are associated with an increased risk of severe NAFLD. These findings suggest that CHI3L1 may serve as a novel biomarker and potential contributor to NAFLD progression, offering insights into the inflammatory and metabolic mechanisms underlying the disease.