In the United States, approximately 2.7 million people have chronic hepatitis C virus (HCV) infection, which is a significant clinical, social, and economic burden for the infected individual and for society as a whole. The outcome of a viral infection is determined by the interaction between the virus and the host immune response. Host genetic factors may also contribute to observed differences in disease prevalence, progression, and treatment response between the African American (AA) and non-Hispanic white (white) populations. Thus, we propose a comprehensive pharmacogenetic study to test the hypothesis that host genetic factors contribute to treatment response and disease progression of HCV infected individuals by examining a large number of immunological candidate genes. Specifically, we propose a two-stage design: initial testing with polymorphic markers spacing at 3-5kb for each of 15 candidate genes, followed by fine mapping of those genes selected based on statistical significance levels, number of significant markers, and results from a second sample. Three sets of samples will be used to evaluate response to therapy and/or disease progression: patients enrolled in the Virahep C trial (N=400), patients excluded from the trial but with disease progression information (N=400), and patients studied at NIDDK Liver Disease Section (N=400). The genetic association results from the latter sample will aid in decision making as to which genes to follow-up with fine mapping. We will also utilize multiple analytic approaches to evaluate associations between candidate genes and outcome variables: evaluating gene-gene interaction, and gene-viral/environmental factor interaction. In addition, we have built in strategies for controlling population stratification by genotyping additional population specific markers and evaluating population structure. By covering important candidate genes comprehensively, utilizing several samples, and explicitly testing possible confounding factors, this proposal maximizes the opportunity to identify the genes and their variants that contribute to the response to therapy and disease progression in HCV infection. As a result of identifying these host factors genetically and investigating their molecular interactions with HCV, we may gain additional insights into HCV pathogenesis and uncover new potential targets for vaccine development and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DK060341-01
Application #
6406935
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M3))
Program Officer
Robuck, Patricia R
Project Start
2001-09-01
Project End
2006-06-30
Budget Start
2001-09-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$276,344
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Jin, Runyan; Cai, Ling; Tan, Ming et al. (2012) Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1. Am J Gastroenterol 107:1675-83
Howell, Charles D; Gorden, Alexis; Ryan, Kathleen A et al. (2012) Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1. J Hepatol 56:557-63
Golden-Mason, Lucy; Bambha, Kiran M; Cheng, Linling et al. (2011) Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 54:1559-69
Evon, Donna M; Esserman, Denise A; Ramcharran, Darmendra et al. (2011) Social support and clinical outcomes during antiviral therapy for chronic hepatitis C. J Psychosom Res 71:349-56
Conjeevaram, Hari S; Wahed, Abdus S; Afdhal, Nezam et al. (2011) Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology 140:469-77
Evon, Donna M; Ramcharran, Darmendra; Belle, Steven H et al. (2009) Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: results of the Virahep-C study. Am J Gastroenterol 104:2949-58
Yee, L J; Im, K; Borg, B et al. (2009) Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection. Genes Immun 10:365-72
Hoofnagle, Jay H; Wahed, Abdus S; Brown Jr, Robert S et al. (2009) Early changes in hepatitis C virus (HCV) levels in response to peginterferon and ribavirin treatment in patients with chronic HCV genotype 1 infection. J Infect Dis 199:1112-20
Mengshol, J A; Golden-Mason, L; Castelblanco, N et al. (2009) Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes. Gut 58:964-73
Dove, Lorna M; Rosen, Raymond C; Ramcharran, Darmendra et al. (2009) Decline in male sexual desire, function, and satisfaction during and after antiviral therapy for chronic hepatitis C. Gastroenterology 137:873-84, 884.e1

Showing the most recent 10 out of 28 publications