Abstract
BackgroundChronic infection with hepatitis C virus (HCV) is a risk factor for liver diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. HCV genetic heterogeneity was hypothesized to be associated with severity of liver disease. However, no reliable viral markers predicting disease severity have been identified. Here, we report the utility of sequences from 3 HCV 1b genomic regions, Core, NS3 and NS5b, to identify viral genetic markers associated with fast and slow rate of fibrosis progression (RFP) among patients with and without liver transplantation (n = 42).MethodsA correlation-based feature selection (CFS) method was used to detect and identify RFP-relevant viral markers. Machine-learning techniques, linear projection (LP) and Bayesian Networks (BN), were used to assess and identify associations between the HCV sequences and RFP.ResultsBoth clustering of HCV sequences in LP graphs using physicochemical properties of nucleotides and BN analysis using polymorphic sites showed similarities among HCV variants sampled from patients with a similar RFP, while distinct HCV genetic properties were found associated with fast or slow RFP. Several RFP-relevant HCV sites were identified. Computational models parameterized using the identified sites accurately associated HCV strains with RFP in 70/30 split cross-validation (90-95% accuracy) and in validation tests (85-90% accuracy). Validation tests of the models constructed for patients with or without liver transplantation suggest that the RFP-relevant genetic markers identified in the HCV Core, NS3 and NS5b genomic regions may be useful for the prediction of RFP regardless of transplant status of patients.ConclusionsThe apparent strong genetic association to RFP suggests that HCV genetic heterogeneity has a quantifiable effect on severity of liver disease, thus presenting opportunity for developing genetic assays for measuring virulence of HCV strains in clinical and public health settings.
Highlights
Chronic infection with hepatitis C virus (HCV) is a risk factor for liver diseases such as fibrosis, cirrhosis and hepatocellular carcinoma
Based on data collected from the Swiss Hepatitis C Cohort Study (SCCS) [15], Bochud and colleagues found that among genotypes 1-4, genotype 3 was significantly associated with faster rate of fibrosis progression (RFP) [16]
Genetic heterogeneity at several nt sites in the HCV Core (n = 8), NS3 (n = 8) and NS5b (n = 9) regions was found to be associated to RFPclass by correlation-based feature selection (CFS) analysis
Summary
Chronic infection with hepatitis C virus (HCV) is a risk factor for liver diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. We report the utility of sequences from 3 HCV 1b genomic regions, Core, NS3 and NS5b, to identify viral genetic markers associated with fast and slow rate of fibrosis progression (RFP) among patients with and without liver transplantation (n = 42). A wide array of host factors and conditions has been reported to affect the RFP and predispose patients with chronic HCV infection to rapid progression of liver fibrosis [8]. To date, studies examining the HCV genetic factors as predictors of RFP in patients with chronic HCV infections have been inconclusive [7,13,17,18,19,20] These observations, taken together with findings indicating associations of genotype with HCVrelated steatosis [13,21] and diversity of intra-host HCV variants with liver disease progression [22], suggest that the genetic composition and diversity of HCV strains may affect RFP in patients with chronic HCV infections
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