A constant finding in the combined interferon and ribavirin treatment of the hepatitis C virus (HCV) is that 40- 70 per cent will have a sustained virologic response to therapy, depending on the viral genotype, 10-20 per cent will have an initial response and require re-treatment, and 25-35 per cent will fail to respond at all. Viral genotype, viral mutation, co-infection with other viruses, age, sex, obesity, hepatotoxins and ethnicity, among other factors, influence treatment outcomes. Part of the variability in response to therapy, however, is likely explained by differences in host genetics. Since interferon (IFN) 1 and 2 are proven therapies for HCV infection, genes that activate and are activated by these cytokines are likely to be important for successful therapy. There have been no studies that systematically examined variations in the genes that make up the type I IFN response pathway and related this to therapeutic response. The majority of patients treated for HCV in Cleveland are seen at specialty clinics in the 4 University-affiliated hospitals. In this project, HIV-negative patients treated between 2000-2011 at these clinics will be genotyped for single nucleotide polymorphisms (SNPs) in key genes of the IFN1 pathway. Out of an estimated 6,000 patients, we anticipate enrolling 1,200 individuals with previous treatment and 1000 prospectively. Allele and haplotype frequencies will then be compared between those with sustained or no virologic response to identify the associated genes. Although hundreds of genes are induced or suppressed by IFN1, for this pilot study we have chosen 80-100 genes known to be key for viral sensing, production of IFN1, signaling or effector mechanisms and modulation of the response. Some 10-20 SNP markers have been identified in each gene based on LD, their known or potential functional role, their allele frequency and their performance in genotyping assays. Values for environmental factors will be obtained from the enrollment interview and patient's charts. Standard and newly developed approaches will be used for single locus and haplotype analyses. The analyses will be multivariable and take into account potential gene-gene interactions and environmental factors influencing the response. In addition, we will control for population stratification and include markers that will allow for analysis of ancestry as a continuous variable. It is expected that this work will permit better pre-treatment stratification and that it will identify genetic factors responsible for the poor responses.

Public Health Relevance

This project will examine the underlying genetic basis for poor responses to treatment for hepatitis C virus infection by means of DNA markers. Differences in the genes of people who do respond will be compared to differences in genes of people who do not respond to therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Koshy, Rajen
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Case Western Reserve University
Schools of Medicine
United States
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