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.