The purpose of this competing renewal is to continue to investigate the host genetic basis for recovery from hepatitis C virus (HCV) infection. There is substantial evidence that there is a host genetic basis for HCV recovery. To investigate this hypothesis, we established a panel that included DNA from 250 persons who cleared HCV infection and 500 matched controls and, in the initial years of R01 DA13324, demonstrated the importance of certain HLA polymorphisms with HCV recovery. In addition, associations were detected between HCV recovery and polymorphisms in certain immune response genes, such as the counter regulatory T cell response gene cytotoxic T lymphocyte antigen 4. Nonetheless, much of the genetic basis for HCV recovery remains unknown. Recent progress in HCV pathogenesis has suggested a number of additional molecular pathways. In addition, completion of the haplotype map of the human genome provides unprecedented power to investigate the complex interactions between the genetics of the immune response and the outcome of HCV infection. We plan to build on these discoveries in forthcoming years of this research program by first doubling the size of what is already the largest DNA panel of HCV recovery. Then, we plan to continue detailed studies of the genetics of interferon regulatory factors, T cell regulatory pathways, and HLA-related mechanisms. Given the established collaborative research networks and the power of scientific methods, we anticipate a high likelihood of success. ? ? ?
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