Proteomic Variation Underlies the Heterogeneous Risk of Metabolic Dysfunction-associated Steatotic Liver Disease for Subsequent Chronic Diseases

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition. Whether and how the plasma proteome underlies the heterogeneous associations between MASLD and subsequent health outcomes remains unclear. Methods This study included 42,508 participants from the UK Biobank. Steatosis was defined by the Fatty Liver Index. Individuals’ MASLD-related proteomic signature was derived from 2911 plasma proteins. Cox models were used to assess the associations of the proteomic signature with eight chronic diseases: liver fibrosis, cardiovascular disease(CVD), chronic kidney disease(CKD), chronic respiratory disease(CRD), dementia, depression, anxiety, and cancers. Adjusted survival curves were fitted to compare the cumulative incidence rate of diseases across quantiles of the proteomic signature; we further adjusted for the steatosis degree and cardiometabolic factors to test whether the association was independent of them. Mediation analyses were performed to identify mediating proteins. Results The proteomic signature was significantly associated with liver fibrosis, CVD, CKD, CRD, and depression in the MASLD population, with adjusted HRs ranging from 1.30 to 4.94. Survival curves showed that individuals with the highest proteomic signature had the highest risk for these five diseases. These risk differences by signature persisted after adjustment for steatosis degree and cardiometabolic factors, except for depression. Proteins including ADM, ASGR1, and FABP4 were identified as common mediators of the association between MASLD and multiple diseases. Mediators of liver fibrosis showed specificity, with CDHR2 being the key protein. Conclusions MASLD patients with the same steatosis severity but different proteomic responses may have different risks for future outcomes. Several key proteins may contribute to the progression of MASLD-related diseases.