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 | $252,007 | Project Dates | null - null |
Fiscal Year | 2018 | 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 Disease (40.0%) Liver Cancer (60.0%) Urinary System (40.0%) |
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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. HIV-1 is pandemic and HBV infection and HBV-related 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) 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) and decreased risk of development of cirrhosis, but not with risk of HCC (An et al. JID 2018), validating etiological role of NTCP. Furthermore, we are investigating the expression and prognostic value of SLC10A1 in HCC tumor-normal tissue pairs by integrating and meta-analyzing eight gene expression datasets (n=1200) derived from GEO and TCGA) data sets. The expression level of SLC10A1 was markedly decreased in HCC tumor tissues compared with corresponding normal tissues in multiple datasets and the low expression was associated with poor survival. We are in the process of detecting SLC10A1 protein expression levels in HCC tissues. We postulate that decreased SLC10A1 may lead to over-accumulation of bile acids, which is potentially cytotoxic to hepatocytes, causing liver inflammation and regeneration. The role of SLC10A1 in HCC tumorigenesis is worthy elucidated. 2) Influence of APOBEC3 genes on cancer initiation and progression. Cytidine deaminases of the human APOBEC3 family (encoded by the APOBEC3 A-H genes) restrict retroviruses and mobile retroelements but they can also hypermutate host ssDNA. We previously identified several genetic variants in the A3G, A3B, A3F and CUL5 of A3-VIf pathway that affect HIV-1 infection or progression. A3B/A3A have been recently recognized as strong endogenous mutagens in multiple cancers. The A3B deletion was associated with elevated risk to breast cancer. Through meta-analysis of transcriptome of cancer tissues and survival data of breast, lung and gastric cancers deposited in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we found that several A3 genes are related with cancer survival, in a cancer specific manner. High A3B expression is associated with worse breast cancer survival but better survival for gastric cancers; high A3F/G expression was protective for gastric cancer survival; A3C showed protection for the breast cancer, but |