Gene expression profiles associated with anaemia and ITPA genotypes in patients with chronic hepatitis C (CH-C).

Anaemia is a common side effect of ribavirin (RBV) which is used for the treatment of hepatitis C. Inosine triphosphatase gene polymorphism (C to A) protects against RBV-induced anaemia. The aim of our study was to genotype patients for inosine triphosphatase gene polymorphism rs1127354 SNP (CC or CA) and associate treatment-induced anaemia with gene expression profile and genotypes. We used 67 hepatitis C patients with available gene expression, clinical, laboratory data and whole-blood samples. Whole blood was used to determine inosine triphosphatase gene polymorphism rs1127354 genotypes (CC or CA). The cohort with inosine triphosphatase gene polymorphism CA genotype revealed a distinct pattern of protection against anaemia and a lower drop in haemoglobin. A variation in the propensity of CC carriers to develop anaemia prompted us to look for additional predictors of anaemia during pegylated interferon (PEG-IFN) and RBV. Pretreatment blood samples of patients receiving a full course of PEG-IFN and RBV were used to assess expression of 153 genes previously implicated in host response to viral infections. The gene expression data were analysed according to presence of anaemia and inosine triphosphatase gene polymorphism genotypes. Thirty-six genes were associated with treatment-related anaemia, six of which are involved in the response to hypoxia pathway (HIF1A, AIF1, RHOC, PTEN, LCK and PDGFB). There was a substantial overlap between sustained virological response (SVR)-predicting and anaemia-related genes; however, of the nine JAK-STAT pathway-related genes associated with SVR, none were implicated in anaemia. These observations exclude the direct involvement of antiviral response in the development of anaemia associated with PEG-IFN and RBV treatment, whereas another, distinct component within the SVR-associated gene expression response may predict anaemia. We have identified baseline gene expression signatures associated with RBV-induced anaemia and identified its functional pathways. In particular, we identified the hypoxia response pathway and the apoptosis/survival-related gene network, as differentially expressed in chronic hepatitis C patients with anaemia.

Functional pathway analysis of genes associated with response to treatment for chronic hepatitis C.

Chronic hepatitis C (CH-C) is among the most common causes of chronic liver disease. Approximately 50% of patients with CH-C treated with pegylated interferon-α and ribavirin (PEG-IFN-α + RBV) achieve a sustained virological response (SVR). Several factors such as genotype 1, African American (AA) race, obesity and the absence of an early virological response (EVR) are associated with low SVR. This study elucidates molecular pathways deregulated in patients with CH-C with negative predictors of response to antiviral therapy. Sixty-eight patients with CH-C who underwent a full course of treatment with PEG-IFN-α + RBV were included in the study. Pretreatment blood samples were collected in PAXgene™ RNA tubes. EVR, complete EVR (cEVR), and SVR rates were 76%, 57% and 41%, respectively. Total RNA was extracted from pretreatment peripheral blood mononuclear cells, quantified and used for one-step RT-PCR to profile 154 mRNAs. The expression of mRNAs was normalized with six 'housekeeping' genes. Differentially expressed genes were separated into up and downregulated gene lists according to the presence or absence of a risk factor and subjected to KEGG Pathway Painter which allows high-throughput visualization of the pathway-specific changes in expression profiles. The genes were consolidated into the networks associated with known predictors of response. Before treatment, various genes associated with core components of the JAK/STAT pathway were activated in the cohorts least likely to achieve SVR. Genes related to focal adhesion and TGF-ß pathways were activated in some patients with negative predictors of response. Pathway-centred analysis of gene expression profiles from treated patients with CH-C points to the Janus kinase-signal transducers and activators of transcription signalling cascade as the major pathogenetic component responsible for not achieving SVR. In addition, focal adhesion and TGF-ß pathways are associated with some predictors of response.

Predictors of health-related quality of life in patients with chronic liver disease.

BACKGROUND: Patient-reported outcomes like health-related quality of life (HRQL) have become increasingly important for full assessment of patients with chronic liver diseases (CLD). AIM: To explore the relative impact of different types of liver disease on HRQL as well as predictors of HRQL domains in CLD. METHODS: Our HRQL databases with Short-Form 36 (SF-36) data were used. Scores for each of SF-36 scales (PF - physical functioning, RP - role functioning, BP - bodily pain, GH - general health, VT - vitality, SF - social functioning, RE - role emotional and MH - mental health, MCS - mental component score, PCS - physical component score) were compared between different types of CLD as well as other variables. RESULTS: Complete data were available for 1103 CLD patients. Demographic and clinical data included: age 54.2 +/- 12.0 years, 40% female, 761 (69%) with cirrhosis. Analysis revealed that age correlated significantly (P < 0.05) with worsening HRQL on every scale of the SF-36. Female patients had more HRQL impairments in PF, RP, BP, GH, VT and MH scales of SF-36 (Delta scale score: 6.6-10.7, P < 0.05). Furthermore, cirrhotic patients had more impairment of HRQL in every scale of SF-36 (Delta scale score: 6.6-43.0, P < 0.05). In terms of diagnostic groups, non-alcoholic fatty liver disease patients showed more impairment of HRQL. CONCLUSIONS: Analysis of this large CLD cohort suggests that a number of important clinicodemographic factors are associated with HRQL impairment. These findings contribute to the full understanding of the total impact of CLD on patients' health.