Identification of Genetic Factors Associated with Infectious Diseases

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Our focus is on two major infectious diseases that impact 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 these infectious 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 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. 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) APOL1 variant alleles associate with reduced risk for opportunistic infections in HIV infection. Because APOL1 variants also dysregulate macrophage differentiation, we investigated the association of APOL1 with opportunistic infections in persons with HIV infection among 440 African Americans with HIV and performed a meta-analysis comprising 4 HIV/AIDS cohorts with 2066 participants. Carriage of two APOL1 variant alleles was associated with 71% reduction in odds of opportunistic infections. We validated this finding in the three HIV prospective cohorts in a meta-analysis. Carriage of two APOL1 variant alleles was associated with a 36% reduction in odds of opportunistic infections. Using a global test combining all four cohorts, carriage of two APOL1 variant alleles was associated with a 50% reduction in odds of opportunistic infections. Subgroup analysis of OI etiological categories revealed that OI protection is mainly attributable to specific protection from fungal infections. The study suggests a broader role of APOL1 variant alleles in innate immunity in vivo. Many patients with severe COVID-19 experience acute kidney injury requiring dialysis. We hypothesize that APOL1 renal high-risk genotypes and sickle cell trait, carried by 13% and 10% of African Americans, are associated with severity of AKI. Accomplishments in HBV-associated liver cancer: 1) We conducted the first study on the impact of the SOAT1 genetic variants and protein expression on HBV-related HCC. A recent proteomics study discovered a lipid metabolism enzyme Sterol O-acyltransferase (SOAT1) involvement in the progression of HCC. To assess the impact of SOAT1 gene variation on risk of HCC occurrence, we genotyped three protein-coding region SOAT1 variants, in 221 biopsy proven HCC patients and 229 healthy individuals. The V323V variant (OR) = 0.58, P = 0.04) and a haplotype TGA (OR = 0.40, P = 0.01) were associated with reduced HCC risk (42-60% lower risks) after adjusting for lipid levels. Using IHC, we found that the protein expression of SOAT1 was significantly increased in the tumor compared with adjacent tissue (P 0.001). This study revealed for the first time association of SOAT1 genetic variation with HBV-HCC susceptibility. This work is under peer-review for publication. 2) Our group also collaborated in a series of studies to identify prognostic biomarkers for HCC prognosis by providing assistance with study design and analysis. We helped identify competing endogenous RNA (ceRNA) network using dysregulated RNAs between tumor and adjacent liver tissues in 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). 3) There is a lack of validation 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 are valuable for development of targeted therapies and prevention once validated. 4) We are in the process identify microRNA markers for HCC diagnosis and prognosis. Detection of miRNA in serum/plasma can be a promising method for early HCC diagnosis enabling effective treatment. Collaborating with South African investigators, we are in the process using RNA-seq technology to systematically uncover the miRNA signatures in a cohort of HBV-associated HCC patients in South Africa. 5) Cytidine deaminases of the human APOBEC3 family (encoded by the APOBEC3 A-H genes) restrict retroviruses and mobile retroelements but also hypermutate host single strand (ss)DNA that may contribute to carcinogenesis. 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. A 29.5-kb DNA germline deletion that fuses the coding region of APOBEC3A with the 3'UTR of APOBCE3B. The APOBEC3B (A3B) deletion is common in Asian but rare in other populations, and is associated with elevated risk to breast cancer. We found this germline A3B deletion was associated with a 2-fold higher HCC risk and 3-5-fold higher risk for one or two-copy deletion compared with no deletion. This result indicates that the common A3B deletion is a major HCC susceptibility locus. We further found that A3B deletion carriers had 2-fold higher risk to have cirrhosis. As the effect of the A3B deletion is so strong and carriage rate is so high in Asian, where HCC prevalence is the highest in the world, an inclusion of the A3B in the polygenic HCC risk prediction model is warranted. We speculate that A3B may modify HCC risk through interacting with key cancer genes including tumor suppressor genes or oncogenes. We particularly explored the relationship between the A3B deletion and tumor suppressor gene TP53. We found a higher TP53 mutation rate among non-carriers of the A3B deletion compared with the two-copy A3B deletion carriers (24% vs. 9%, p=0.02), suggesting A3B presence may cause TP53 mutation, and that its absence reduces the chance of mutation, consistent with the A3B role as a hypermutator, a novel mechanism that links between A3B and HCC through TP53.