Molecular mechanisms involved in the interaction effects of alcohol and hepatitis C virus in liver cirrhosis.
The mechanisms by which alcohol consumption accelerates liver disease in patients with chronic hepatitis C virus (HCV) are not well understood. To identify the characteristics of molecular pathways affected by alcohol in HCV patients, we fit probe-set level linear models that included the additive effects as well as the interaction between alcohol and HCV. The study included liver tissue samples from 78 patients, 23 (29.5%) with HCV-cirrhosis, 13 (16.7%) with alcohol-cirrhosis, 23 (29.5%) with HCV/alcohol cirrhosis and 19 (24.4%) with no liver disease (no HCV/no alcohol group). We performed gene-expression profiling by using microarrays. Probe-set expression summaries were calculated by using the robust multiarray average. Probe-set level linear models were fit where probe-set expression was modeled by HCV status, alcohol status, and the interaction between HCV and alcohol. We found that 2172 probe sets (1895 genes) were differentially expressed between HCV cirrhosis versus alcoholic cirrhosis groups. Genes involved in the virus response and the immune response were the more important upregulated genes in HCV cirrhosis. Genes involved in apoptosis regulation were also overexpressed in HCV cirrhosis. Genes of the cytochrome P450 superfamily of enzymes were upregulated in alcoholic cirrhosis, and 1230 probe sets (1051 genes) had a significant interaction estimate. Cell death and cellular growth and proliferation were affected by the interaction between HCV and alcohol. Immune response and response to the virus genes were downregulated in HCV-alcohol interaction (interaction term alcohol*HCV). Alcohol*HCV in the cirrhotic tissues resulted in a strong negative regulation of the apoptosis pattern with concomitant positive regulation of cellular division and proliferation.
Mas
Valeria R
VR
Hume-Lee Transplant Center, Division of Transplant, Department of Surgery, Virginia Commonwealth University Health System, Richmond, Virginia 23298-0057, USA. vmas@mcvh-vcu.edu
Fassnacht
Ryan
R
Archer
Kellie J
KJ
Maluf
Daniel
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D016000:Cluster Analysis; D000431:Ethanol / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D000431:Ethanol
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