Identification of Genetic Factors Associated with Infectious Diseases

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

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 it is associated with worse outcome for lung and gastric cancer. We are in the process of validating the A3 gene and gastric cancer association and aim to validate A3 gene variant signatures in several other cancers. To elucidate A3B/A3A role in tumorigenesis, we are taking advantage of a natural A3B gene deletion polymorphism that is Asian-specific. We found that A3B deletion may not affect risk of hepatocellular carcinoma (HCC) by comparing 327 HCC cases with over 1000 HBV chronic carriers. We are assessing the pattern of A3B del and A3 gene expression in additional 300 HCC tissues samples for their impact on clinical characteristics and prognosis. We also found a novel association of a functional SNP affecting the APOBEC3A/B expression with AFP levels in HCC patients, implicating APOBEC3 role in HCC development. 3) Ki-67 (MKI67) is a gene that regulates cell proliferation, differentiation, and growth. Through public database analysis, we found that MKI67 expression level was associated with TGFB1 expression in liver cancer tissues and higher MKI67 expression level had a worse survival in patients with HBV-related HCC. Our result suggests that MKI67 expression level may predict the clinical outcomes of HCC. 4) We measured oxidative stress levels (8-hydroxy-2'-deoxyguanosine (8-OHdG) ) in 89 HCC tissues in patients receiving preoperative transcatheter arterial chemotherapy (TAC) and studied its association with prognosis. We found that preoperative TAC might postpone postoperative HCC relapse through suppressing oxidative stress. 5) we proposed a case-control study to use circulating microRNA's as a diagnostic tool for hepatocellular carcinoma in a hyper endemic HIV setting in an Africa population. 6) we reviewed host and viral genetic variation in HBV-related HCC. The observed individual variance in development of HCC is attributable to differences in HBV genotype and mutations, host predisposing germline genetic variations, the acquisition of tumor-specific somatic mutations, as well as environmental factors. We comprehensively reviewed and assessed the evidence of germline variants and somatic mutation and virial genetic factors contributing to HCC. 7) HIV-positive individuals are at increased risk for kidney disease resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, I participants in an international panel of experts in nephrology, renal pathology, and infectious diseases to describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease and define best practices for the prevention and management of kidney disease in HIV-positive individuals. 8) I reviewed potential interaction mechanisms between HIV-1 and APOL1. APOL1 variant proteins and HIV accessory proteins implicated in HIVAN may target the same or related intracellular pathways in podocytes, such as interleukin 1b and transcription factor EB, while increased circulating factors such as interferon due to uncontrolled HIV infection may drive APOL1 gene transcription in podocytes. 9) Current therapies on renal diseases fail to halt the progressive decline in kidney function, in one aspect due possibly to failure to address critical pathologic processes driven in podocytes by the APOL1 renal risk genetic variants. We described five mechanisms that APOL1 mediating kidney cell injury (increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress) and suggested possible novel therapeutic approaches.