HEPATITIS C CLEARANCE AND HOST GENETIC FACTORS

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DESCRIPTION: (Applicant's Abstract) The candidate is completing a three year Infectious Diseases fellowship and has devoted the last two years to studying associations of the human leukocyte antigen complex to hepatitis B virus outcomes in a multi-cohort study. Through this grant, the candidate will use molecular genetics tools in an epidemiologic setting and will thus bridge the gap between the epidemiologists and basic scientists in an effort to understand immunopathogenic mechanisms of infectious diseases. Long-term, the candidate would like to establish herself as a faculty member interested in understanding infectious disease outcomes by examining the genetically-determined variability of the host response. In particular, in the short-term, this candidate is interested in studying host genetic factors that affect hepatitis C outcomes to elucidate mechanisms of hepatitis C virus pathogenesis, which eventually may have therapeutic and vaccine implications. The work will be performed under the guidance of Dr. David Thomas who has expertise in hepatitis C and epidemiology. In collaboration with Dr. David Vlahov, the epidemiologist who established the ALIVE cohort, and with Dr. Mary Carrington, a leader in the field of genetics, the candidate will have the collaborative resources necessary for the successful completion of this project. The candidate will complement her research by attending 2 hours per week of infectious diseases and hepatitis related conferences, attending weekly hepatitis C research meetings, and seeing patients in an infectious diseases/hepatitis clinic one half-day per week. She also plans to take courses in epidemiology, genetics, and virology. Over 170 million people worldwide are infected with hepatitis C virus (HCV), 85 percent of them have a persistent infection and the remainder clear the virus. This heterogeneous outcome difference is not explained by viral or environmental factors. As has been shown in other chronic viral infections, it is likely that host factors, which may be genetically programmed determine these outcomes. In the past, these host-virus interactions have been difficult to explore because of limited knowledge of HCV biology and lack of molecular tools to explore the human genome. However, HCV biology is unfolding and the recent advances in molecular biology permit detection of human genomic variability on a large scale. Using the ALIVE cohort of injection drug users, the candidate will study 131 individuals who have cleared the virus and 262 matched controls with persistent HCV infection. She will test polymorphisms in the human leukocyte antigen alleles and putative pathogenic genes for distortions in allele frequency between the clearance and persistently infected individuals. Where possible, the allele frequencies will be checked for Hardy-Weinberg equilibrium distortions. Chi-square analysis and univariate and multivariate conditional logistic regression will be performed. The associations will also be assessed with regards to HCV genotype. Success is anticipated since the cohort is well-characterized, the molecular tools exist, and the collaborations have proven to be productive in HBV studies.