ZIA BC 010297 (ZIA) | |||
---|---|---|---|
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 | $317,486 | Project Dates | 10/01/1997 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (1.0%) Cancer (100.0%) Digestive Diseases (15.0%) Genetic Testing (25.0%) Herpes - Other (35.0%) |
Cervical Cancer (5.0%) Kaposi Sarcoma (30.0%) Kidney Cancer (1.0%) Kidney Disease (20.0%) Liver Cancer (15.0%) Sarcoma (30.0%) Urinary System (20.0%) Wilm's Tumor (1.0%) |
||
Research Type | |||
Exogenous Factors in the origin and cause of cancer Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
|||
Abstract | |||
This project's 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 both targeted gene and genome wide association study (GWAS) approaches, including Illumina and Affymetrix chip technologies, to discover genes associated with HIV-1, HBV infection and HBV-associated liver cancer. Accomplishments 1) HIV-1 resistant APOBEC3 (A3) genes. Six of the seven A3 genes (including A3B, A3G and A3F) are human innate resistance factors that confer resistance to HIV-1 by causing hypermutation of viral RNA. Previously we discovered genetic factors in the APOBEC3G and CUL5 pathway that affect AIDS progression. The seven APOBEC3 genes (A-H) are clustered in a 100 kb region in chromosome 22. We assessed the influence of the genetic variants and haplotype in all APOBEC3 genes (A-H) on HIV-1 infection and disease courses. Besides the associations we previous found in A3G and A3B, we have identified A3F genetic variants that retard AIDS progression. In vitro, APOBEC3F strongly inhibits HIV-1 and is partially resistant to HIV-1 vif, unlike APOBEC3G. We found that codon-changing variants rs5750728 (intronic or codon-changing 78 V/A in different isoforms) and 231 I/V were associated with protection from progression to AIDS in European Americans. We found that rs5750728 alters binding to nuclear proteins in HeLa cells, suggesting a regulator role. In collaboration with researchers at Johns Hopkins University, the interaction of the APOBEC3F with HIV-1 vif was evaluated; the carrying codon-changing SNP 231 I/V was shown to confer stronger resistance to vif that degrades A3F, possibly leading to more abundant A3F to inhibit HIV-1. It is of interest that in the alignment of A3F and vif sequences, the A3F region carrying 231 I/V appears to either be mimicked by or has co-evolved with HIV-1 vif. This may reveal a mechanism allowing HIV-1 to evade A3F by adapting to host A3F sequences. 2) ZNRD1 and HIV-1 infection. We investigated the effect of the SNPs in the ZNRD1 region on HIV-1 infection and progression in five U.S-based HIV-1 longitudinal cohorts. A haplotype in the ZNRD1 gene showed significant association with host restriction to HIV-1 acquisition. The functional relevance of the associated variant was demonstrated in a gene reporter assay that showed one promoter variant (rs3132130) increased the ZNRD1 gene expression. Further, in a DNA-protein interaction assay, the variant also confers differential allele-specific binding to nuclear proteins. Our findings provide novel evidence of significant roles of ZRND1 in modulating HIV/AIDS. This work has been published in Journal of Infectious Diseases, June 2014. 3) GWAS of HBV and HCC. HBV infection is extremely prevalent in China (HBsAg carrier rate was 7% in 2006). Many HBV infected patients develop cirrhosis and hepatocellular carcinoma (HCC). MGE has an ongoing collaborati" |