Identification of Genetic Factors Associated with Infectious Diseases

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Our 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 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) APOL1 associations with renal disease in a setting of HIV infection. HIV-positive individuals are at increased risk for kidney diseases, including HIV-associated nephropathy (HIVAN), non-collapsing focal segmental glomerulosclerosis (FSGS), immune-complex kidney disease, ]as well as kidney injury resulting from prolonged exposure to antiretroviral therapy. APOL1 protein confers resistance to most forms of Trypanosoma brucei, the cause of trypanosomiasis, by lysing the parasite. Two coding variants in the APOL1 gene extend the resistance to T. brucei strains that cause human trypanosomiasis, but at the cost of increasing risk of chronic and end stage kidney disease. The risk is particularly high for persons with untreated HIV infection (odds ratios 29 and 89 in African Americans and South Africans, respectively) where the lifetime risk of developing HIVAN, a progressive form of kidney disease, is 50%. With the advent of antiretroviral therapy (ART), HIVAN prevalence has waned, and has been replaced with ART-treated patients, FSGS and numerous forms of immune complex disease have been reported. In addition, patients lacking sustained suppression of HIV replication have been reported to have more rapid decline in kidney function.) An international panel of experts in the genetics and genomics of HIV-associated kidney disease and the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals was organized by KDIGO to define best practices for the prevention and management of kidney disease in HIV-positive individuals. As co-chair of the workshop for Genetics/Genomics of Kidney Disease in the setting of HIV we formalized for publication best practices and knowledge gaps in our understanding of APOL1 in kidney disease in a setting of HIV infection. 2) 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 (OR 0.37, p = 0.005) and decreased risk of development ofcirrhosis (OR 0.18, P = 0.01), but not with risk of HCC. 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 6 out of 8 datasets (meta-p-value 0.0001, fold change 1.03-9.6). Low expression in tumor tissue was associated with poor survival (Log-rank p-value0.001). 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, whether involving its HBV receptor function, remain to be addressed. 3) APOL1 risk variants are associated with chronic kidney disease (CKD) in children with perinatal HIV infection (PHIV). We found that children and youth with PHIV who carried APOL1 high risk genotypes had a 3.5-fold increased odds of CKD compared to those with APOL1 low risk genotypes. This study has important implications for children in sub-Saharan Africa where PHIV infection is prevalent and many children are under-treated. 4) Association of Coxiella birnetii virus with non-Hodgkin B-cell lymphoma (NHL) in HIV-infected patients. About 3% of the USA population have antibodies to Coxiella burnetii, the causative agent of is Q fever. Previously, a study of 1468 French patients found a 25-fold increase in NHL). HIV infection is also linked to NHL and a link between HIV infection and higher prevalence of C burnetii has been found in some but not other studies. We hypothesized that anti-C burnetii antibody prevalence would be higher in patients with AIDS-related NHL. Using stored plasma and serum samples from two prospective HIV cohort studies, we found that C burnetii seroprevalence was not associated with incident or prevalent NHL cases in a setting of HIV infection, which we reported in the journal Blood. 5) 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 are also recognized as strong endogenous mutagens in cancers. A3B/A3A have been recently recognized as strong endogenous mutagens in multiple cancers. For example, 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 virus 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.