ZIA BC 010297 (ZIA) | |||
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Title | Identification of Genetic Factors Associated with Infectious Diseases | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Winkler, Cheryl | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $313,024 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (1.0%) Cancer (100.0%) Digestive Diseases (60.0%) Genetic Testing (25.0%) Herpes - Other (35.0%) |
Kidney Cancer (20.0%) Kidney Disease (40.0%) Liver Cancer (60.0%) Urinary System (40.0%) Wilm's Tumor (10.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Our focus is on two infectious diseases that continue to have tremendous impact on global health. Human Immunodeficiency Virus (HIV) is pandemic and Hepatitis B Virus (HBV) infection and HBV-associated hepatocellular carcinoma (HCC) is prevalent in East Asia, globally affecting millions of people and having no cure. The objective of this project is to identify host factors that contribute to the occurrence and development of these, and potentially other, infectious diseases. We aim to identify host genetic factors that affect host innate restriction or susceptibility in acquisition, replication, and pathogenesis of viral pathogens, and carcinogenesis, the mechanisms of which are not fully understood. The identification of host proteins involved in viral replication, in innate or acquired immunity, or in carcinogenesis pathways will provide critical insights for the rational development of antiviral drugs and effective vaccines. Our strategy is to search for genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the variant-containing gene as conferring restriction or susceptibility to infection or progression. We are using targeted gene, genome wide association study (GWAS), and functional approaches to discover genes associated with HIV-1, HBV infection and HBV-associated liver cancer. We have also formed international collaborations with researchers in South Africa and China to mentor fellows, build capacity, and perform research that address important public health questions (i.e. HIV in South Africa and HBV-associated liver cancer in China). Accomplishments: 1) APOL1 associations with renal disease in a setting of HIV infection. HIV-positive individuals are at increased risk for kidney diseases, including HIV-associated nephropathy (HIVAN), non-collapsing focal segmental glomerulosclerosis (FSGS), immune-complex kidney disease, ]as well as kidney injury resulting from prolonged exposure to antiretroviral therapy. APOL1 protein confers resistance to most forms of Trypanosoma brucei, the cause of trypanosomiasis, by lysing the parasite. Two coding variants in the APOL1 gene extend the resistance to T. brucei strains that cause human trypanosomiasis, but at the cost of increasing risk of chronic and end stage kidney disease. The risk is particularly high for persons with untreated HIV infection (odds ratios 29 and 89 in African Americans and South Africans, respectively) where the lifetime risk of developing HIVAN, a progressive form of kidney disease, is 50%. With the advent of antiretroviral therapy (ART), HIVAN prevalence has waned, and has been replaced with ART-treated patients, FSGS and numerous forms of immune complex disease have been reported. In addition, patients lacking sustained suppression of HIV replication have been reported to have more rapid decline in kidney function.) An international panel of experts in the genetics and genomics of HIV-associated kidney disease and the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals was organized by KDIGO to define best practices for the prevention and management of kidney disease in HIV-positive individuals. As co-chair of the workshop for Genetics/Genomics of Kidney Disease in the setting of HIV we formalized for publication best practices and knowledge gaps in our understanding of APOL1 in kidney disease in a setting of HIV infection. 2) HBV receptor NTCP genetic variant and risk to HBV infection. Sodium taurocholate cotransporting polypeptide (NTCP/SLC10A1) was recently identified as the functional cell receptor for HBV. The S267F variant causes loss of HBV receptor. We assessed the association of NTCP S267F in over 1000 patients with different HBV infection outcomes: HBV resistance, clearance, chronic infection, cirrhosis, and HCC. S267F was associated with increased resistance to HBV infection (OR 0.37, p = 0.005) and decreased risk of development of cirrhosis |