IDENTIFICATION OF CANDIDATE GENE POLYMORPHISMS ASSOCIATED WITH INFECTIOUS DISEASE

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We are utilizing a candidate gene approach to identify polymorphic loci that may have a role in viral infection and disease progression. Identification of such loci provides a valuable tool for the identification of host-cellular components that are operative in viral infection, replication, viral assembly, and immune regulation of the infection. Defining the mechanisms by which host factors restrict viral disease process will advance our understanding of viral pathogenesis and may lead to possible therapuetic interventions. Differences in mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for both HIV and hepatitis B virus (HBV). To date we have established nearly 6000 cell lines from participants enrolled in natural history cohorts of the three major HIV risk groups, hemophiliacs, homosexuals, and intravenous drug users. We have also initiated cohort studies to investigate the role of host genetic factors in hepatitis C virus (HCV) and HBV clearance and pathology. Our approach has been: 1) establish cell lines from study participants as a renewable source of DNA; 2) identify single nucleotide polymorphisms (SNPs) or insertion/deletion (indel) mutations in candidate genes; 3) screen SNPs in large cohorts and in cases and controls; and 4) use categorical and survival analyses to test for associations between genotypes and phenotype.To date our group has contributed to the identification of 6 genes that affect infection, the rate of progression to AIDS, and specific AIDS outcomes. Several variants in genes involved in immune response to HIV, viral transcription, and viral assembly have been identified by our group which also have been shown to delay or accelerate progression to AIDS. Although the effect of each of these variants is small, together they account for approximately 30-50% of long-term AIDS survivors. Using the genetic analysis of HIV-1 as a model for association analysis of complex diseases which have both genetic and environmental components, we are employing a similar strategy to investigate the host genetic contributions to outcomes following infection with the hepatitis viruses, HCV and HBV. These important human viral infections have global distributions and extremely high prevalence rate in some regions of the world and among certain risk groups and cause considerable morbidity and mortality. They are also associated with increased risk of liver cancer, and have similar, although not identical, risk factors. The pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes. We are using a candidate gene approach to elucidate the genetic basis for the extensive variation observed within risk groups in viral clearance, liver disease progression, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS - candidate genes, gene mapping, Genetic Susceptibility, HIV, microsatellites, - Human Tissues, Fluids, Cells, etc.