Our focus is on two major infectious diseases have enormous impact on global health. HIV-1 is pandemic and HBV infection and HBV-related hepatocellular carcinoma (HCC) is prevalent in East Asia and sub-Saharan Africa, globally affecting millions of people. Our objective is to identify genetic factors that contribute to the occurrence and development of theseinfectious diseases. 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 identify genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the variant-containing gene using targeted gene, genome wide association study (GWAS), and functional approaches. We have 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 in HIV disease: 1) APOL1 renal risk variants interact strongly with HIV to cause HIV-associated nephropathy with odds ratios ranging from 29 in African Americans to 89 in southern Africa. In vitro studies suggest that APOL1, an innate immune factor, impedes HIV replication by several mechanisms, including a pathway involving secretion of Vif in microvesicles and degradation of Vif in lysosomes. We hypothesized that APOL1 coding variants might attenuate the protective effect of ancestral APOL1 resulting in higher viral burden or increased transmission of HIV. This could possibly contribute to the high burden of HIV disease in sub-Saharan African were APOL1 risk variants are very common, with allele frequencies ranging from 10-50%. We therefore conducted genetic epidemiological association analyses of HIV patients with longitudinal follow-up spanning the pre- and post-antiretroviral treatment eras. We found that the variants do not increase the risk of HIV-1 infection and are not associated with viral load or progression to AIDS. This finding suggests that APOL1 variants do not contribute to the higher prevalence of HIV infections in sub-Saharan Africa or in African Americans (An et al. Front Immunol, 2019). 2) Because APOL1 variants also dysregulate macrophage differentiation, we have explored its role in the development of optimistic infections in persons with HIV infection. Our findings suggest that APOL1 variants may confer protection specifically against fungal opportunistic infections. We are now replicating this finding in independent HIV natural history cohorts. Accomplishments in HBV-associated liver cancer: 1) Genetic variants in the HBV receptor NTCP ( modify risk to HBV infection and progression to liver cirrhosis. Sodium taurocholate co-transporting polypeptide (NTCP/SLC10A1) was recently identified as a cell receptor for HBV cell entry. The S267F variant causes the loss of the HBV receptor function. We assessed the association of NTCP/SLC10A1 S267F in over 1000 patients with distinct HBV infection outcomes: HBV resistance, clearance, chronic infection, cirrhosis, and HCC. The NTCP/SLC10A1 S267F coding variant was associated with increased resistance to HBV infection and decreased risk of development of cirrhosis, but not with modified risk of HCC (An et al. JID 2018), validating the etiological role of the NTCP/SLC10A1 receptor as a primary HBV receptor. NTCP/SLC10A1 antigonists might provide therapeutic benefit in patients with chronic HBV infection by decreasing progression to liver cirrhosis. We are also investigating the expression and prognostic value of NTCP/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 NTCP/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 NTCP/SLC10A1 protein expression levels in HCC tissues. We postulate that decreased NTCP/SLC10A1 may lead to over-accumulation of bile acids, which is potentially cytotoxic to hepatocytes, causing liver inflammation and regeneration. 2) Mildly elevated bilirubin levels are reported to be associated with decreased risk of non-alcoholic fatty liver disease (NAFLD), a risk factor for HCC; however, the direction of causality is unknow. In a collaborative study with colleagues in China, we tested the hypothesis that genetically elevated plasma bilirubin levels are causally related to reduced risk of NAFLD in 403 participants with liver ultrasonography. NAFLD was diagnosed in 19% of study participants. Two variant alleles in UGT1A1 10-12% of the variance in bilirubin levels. In a multivariant analysis using a Mendelian randomization approach, we found that UGT1A1 genotypes did not associated with NAFLD. We also found that plasma bilirubin levels were not associated with risk of NAFLD. These two results suggest that bilirubin is unlikely to be causally related to NAFLD risk (Luo et al, Front Genet, 2018). 3) Our group also contributed to a series of studies by our Chinese colleagues to identify prognostic biomarkers for HCC prognosis by providing assistance with study design and analysis. Ki-67 (MKI67) is a gene that regulates cell proliferation, differentiation, and growth. Through public database analyses, we found that MKI67 expression level was associated with TGFB1 expression in liver cancer tissues and higher MKI67 expression level was associated with poorer survival in patients with HBV-related HCC, suggesting that MK167 expression levels may predict clinical outcomes of patients with HBV-related HCC (Yang et al. Cancer Manag Res, 2018). A second study was to identify competing endogenous RNA (ceRNA) network using dysregulated RNAs between tumor and adjacent liver tissues in the Cancer Genome Atlas (TCGA) and to investigate underlying prognostic factors in HCC patients. This study constructed a ceRNA network and gene set enriched in pathways of the cell cycle, cell division, and cell proliferation. The prognostic signature may provide an independent tool for prediction of HCC survival (Liao et al., J Cancer, 2019). 4) There is lack of validations across limited transcriptomic studies in HBV-related HCC. We performed a meta-analysis to assess changes in gene expression patterns by integrating HBV-HCC samples from TCGA and GEO datasets. Our analysis revealed that over 500 differentially expressed genes (DEG) were shared across all datasets, indicating that approximately 8% of differentially expressed genes from TCGA HBV-HCC are replicated across studies. The identified pathways and genes may be useful for development of targeted therapies and prevention once validated, as we are doing in our South African cohort of HBV-associated HCC. 5) 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 single strand (ss)DNA. 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 has been associated with elevated risk to breast cancer. We found that a functional SNP affecting APOBEC3A/B expression was associated with AFP levels in HCC patients, implicating APOBEC3 role in HCC development. We are now extending our investigation to the interaction of APOBEC3B deletion and HCC hot somatic mutations of TP53 and TERT.
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