Demarcating the Development of Cirrhosis and Its Complications via Plasma Proteomic Features in an Asymptomatic Population

The early detection of liver cirrhosis and its complications is a conundrum in clinical practice. We aim to address this conundrum using proteomic features of plasma. A total of 52,891 participants without cirrhosis or its complications were recruited from the UK Biobank longitudinal population cohort. We identified GDF15, CDCP1, ADGRG1, GGT1, HGF, MFAP4, and THBS2 from 2923 plasma proteins and developed proteomic models to predict early cirrhosis and its complications occurring at 5, 10, and over 10 years. These protein markers were validated to be associated with liver fibrosis in an external liver biopsy cohort. High levels of GDF15 and GGT1 were associated with an increased risk of developing cirrhosis and its complications. The two proteins began to change at least 13 years before the diagnosis of cirrhosis and its complications. Transcriptomic analysis delineated the cellular localization of these proteins in the liver and demonstrated their expression changes during fibrosis progression across different etiologies. Mendelian randomization analyses further supported a potential causal effect of GGT1 on cirrhosis.