Translational genomics, transcriptomics and metabolomics analyses of the metabolic effects of chronic hepatitis C infection and their clinical implications

Abstract

Background: The hepatitis C virus (HCV) relies on host lipid pathways for its life cycle, leading to metabolic consequences including hypocholesterolemia, insulin resistance and hepatic steatosis. These sequelae have varying clinical implications, including poorer sustained viral response (SVR) to pegylated interferon/ribavirin (PEG/RBV) therapy, increased risk of hepatic fibrosis and residual risk of liver disease (eg fibrosis, steatosis) and complications (eg hepatocellular carcinoma), even after SVR. Aims: To define host genomic and metabolomic profiles associated with hypocholesterolemia, hepatic steatosis, hepatic fibrosis and hepatic inflammation in chronic HCV infection, and to assess their clinical impacts. Methods: Genome wide association studies, candidate gene studies, microarray based mRNA transcription profiling, liquid chromatography/mass spectrometry metabolomic assays, multivariable regression models (MVR). Results: In HCV genotype 1 (G1), IL28B genotype is the only common variant associated with LDL-C levels. LDL-C levels remain significant predictors of SVR. Host IL28B and PNPLA3 polymorphism are significant host determinants of susceptibility to hepatic steatosis in chronic HCV G1 infection. Lower PNPLA3 genotype frequency in African American (AA) patients may explain their lower frequency of hepatic steatosis relative to Caucasian Americans, despite greater metabolic risk factors in AA patients. PNPLA3 was associated with Mallory bodies and lobular inflammation (a pattern seen in non-alcoholic fatty liver disease) but not fibrosis. Gene expression enrichment associated with PNPLA3 genotype and varied phenotypes of histopathological injury include a number of novel genetic associations as well as transcripts previously identified which warrant further investigation. HCV perturbs the distal cholesterol synthesis pathway in a HCV genotype-specific manner but the levels of the proximal sterol lanosterol, which has important cholesterol regulation effects, is preserved. Conclusions: Taken together, these translational genomics and metabolics studies provide insights into the nature of host-virus metabolic interactions in chronic HCV and their clinical sequelae.