The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin

<p>Abstract</p> <p>Background</p> <p>Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.</p> <p>Methods</p> <p>Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.</p> <p>Results</p> <p>The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.</p> <p>Conclusions</p> <p>IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.</p

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Developing a 'traffic light' test with potential for rational early diagnosis of liver fibrosis and cirrhosis in the community

Background: Liver disease develops silently and presents late, with often fatal complications. Aim: To develop a `traffic light' test for liver disease suitable for community use that could enhance assessment of liver risk and allow rational referral of more severe disease to specialist care. Design and setting: Two cohorts from Southampton University Hospital Trust Liver Unit: model development and a validation cohort to evaluate prognosis. Method: A total of 1038 consecutive liver patients (inpatient and outpatient) (development n = 397, validation n = 641) for whom the relevant blood tests had been performed, were followed for a mean of 46 months (range 13-89 months). Blood tests for: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), and platelet count were combined in a diagnostic algorithm to stage liver disease. Results: A simple clinical rule combined: HA, P3NP, and platelet count into a `traffic light' algorithm, grading the results red - high risk, amber - intermediate risk, and green - low risk. In the validation cohort, no green subjects died or developed varices or ascites (n = 202); in the amber group, 9/267 (3.3%) died, 0/267 developed varices, and 2/267 (0.7%) developed ascites; in the red group, 24/172 died (14%), 24/172 (14%) developed varices, and 20/172 developed (11.6%) ascites. Survival was reduced in red (P&lt;0.001) and amber (P&lt;0.012) groups compared with green. Conclusion: A simple blood test triages liver disease into three prognostic groups; used in the community, it could enhance the management of risk factors in primary care and rationalise secondary care referrals, including the many patients with fatty liver and relatively minor elevations in alanine transaminase