Liver failure due to chronic hepatitis C virus infection is a
Liver failure due to chronic hepatitis C virus infection is a major cause for liver transplantation worldwide. expression of patients at risk of developing severe fibrosis. Significantly, alterations in gene expression occur prior to histologic evidence of liver disease 25122-41-2 manufacture progression, suggesting that events which occur during the acute phase of infection influence patient outcome. Additionally, a common precursor state for BCL3 different severe clinical outcomes was identified. Hence, based on this patient cohort, incidence of severe liver disease is a process initiated early during HCV infection of the donor organ. The probable cellular network at the basis of the initial transition to severe liver disease 25122-41-2 manufacture was identified and characterized. (12). Additionally, we identified 11 genes associated with cancer, specifically those involved in cell cycle control such as retinoblastoma-like 2 (RBL2) and cyclin-dependent kinase inhibitor 3 (CDKN3), and regulators of cellular differentiation. As cancer-related genes associated with cellular proliferation steadily increased, those associated with cell cycle checkpoint control and cell type specification were downregulated. This indicates that patients with progressive liver disease experience a loss of differentiation and checkpoint cell cycle arrest, consistent with the concordant gradual increase in proliferative capacity. This also suggests a mechanism by which chronic HCV infection contributes to tumorigenesis of hepatocellular carcinoma Gene signature characterizing a precursor state for severe liver disease The SVD-MDS method used in the analysis presented in figures 2GCJ and figure S1GCJ allows the computation of two additional parameters aside from the Kruskal stress (information-loss during dimensionality reduction): external isolation (the arithmetic average inter-group distance) and internal cohesiveness (the intra-group distance). Both parameters determined for the analyses peak 3C6 months post-OLT (Figure 4A), indicating that the signatures derived from these time-categories generate the relative maximal resolution. Hence, the early stages of HCV reinfection best characterize overall clinical outcome. We then used the time-specific analysis to define a gene expression pattern-based distance measure between any of the individual groups and with combined G2345 and G345, as well as G45 longitudinal analysis. To investigate severe liver disease progression according to time and patient outcome, these measures were then subjected to k-means clustering (13) using inter-group distances as additional constraints. This analysis indicates the existence of a common precursor state G345 for all progressor groups (Figure 4B, red), from which all three adverse outcomes split individually. This precursor state is comprised of 35 DEG (Table 2), which distinguish the transformation to a progressive disease outcome long before histological or clinical evidence of severe disease. Figure 4 The cellular network of HCV-induced progression to severe liver disease Table 2 Differentially expressed genes associated with transition to progressive disease In the absence of time-resolved samples from healthy, non-HCV patients, we were not able to determine whether a common G2345 (Figure 4B, black) state exists or how this hypothetical intermediate state would relate to G2 and G345. More importantly, the predicted common G345 precursor state confirmed our observation that eventual severe liver disease is programmed early post-OLT, and in combination with the time-specific analyses described above, identified DEG distinguishing progressors and non-progressors within 6 months of transplantation. Using IPA, we generated a network of directly interacting molecules based on the network analysis of the transitional signature and the G345e time-specific gene sets (Figure 4C, Figure S2). We confirmed that repression of genes involved in cell cycle regulation and stress responses (cyclin D1, CCND1, and X-box binding protein, XBP1), innate immunity (signal transducer and activator of transcription 1, STAT1), and antigen presentation (HLA-A, HLA-G, and HLA-E) characterize transition to a progressive phenotype. Additionally, collagen upregulation was detected within several months of transplantation, months or years before fibrosis is histologically detectable. 25122-41-2 manufacture Coupled with our finding that the statistically significant upregulation of collagen expression correlates with disease progression over time, this indicates that collagen transcription is both critical to the mechanism of fibrogenesis and potentially useful as a predictive marker to identify patients at risk of HCV-induced liver disease prior to extensive collagen deposition and associated liver damage. Discussion Investigating the influence of transcriptional profiles on clinical outcome in patients following transplantation.