Identification of Genetic Factors Associated with Infectious Diseases

与传染病相关的遗传因素的鉴定

• 批准号: 9556253
• 负责人: Cheryl Winkler
• 金额: $ 43.58万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556253
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Acquired Immunodeficiency Syndrome; Address; Affect; Africa South of the Sahara; African American; Age; Aging; Antibodies; Antigen-Antibody Complex; Antiviral Agents; Asians; B-Cell NonHodgkins Lymphoma; Bile Acids; Blood; CUL5 gene; Cancer Etiology; Carcinogenesis Mechanism; Cardiovascular Diseases; Cardiovascular system; Characteristics; Child; China; Chronic; Chronic Disease; Chronic Hepatitis B; Chronic Kidney Failure; Cirrhosis; Clinical; Clinical Management; Code; Cohort Studies; Collaborations; Communicable Diseases; Coxiella; Coxiella burnetii; Cytidine Deaminase; Data; Data Set; Deposition; Development; Diagnosis; Disease; Early Diagnosis; Educational workshop; End stage renal failure; Environmental Risk Factor; Epigenetic Process; Exposure to; Family; Far East; Focal Segmental Glomerulosclerosis; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; Hepatitis B; Hepatocyte; High Prevalence; Human; Immune Complex Diseases; Individual; Infection; Inflammatory; Injury; Integration Host Factors; International; Journals; Kidney; Kidney Diseases; Knowledge; Lead; Link; Liver Regeneration; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mentors; Meta-Analysis; Metabolic; Modification; Mutagens; Na(+)-taurocholate-cotransporting peptide; Natural Immunity; Normal tissue morphology; Odds Ratio; Organ; Other Genetics; Outcome; Parasites; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Penetrance; Perinatal; Persons; Pharmacotherapy; Plasma; Population; Predisposition; Premature aging syndrome; Prevalence; Prevention; Primary carcinoma of the liver cells; Process; Proteins; Public Health; Publications; Q Fever; Receptor Cell; Renal function; Reporting; Research; Research Personnel; Resistance; Retroelements; Retroviridae; Risk; Role; Sampling; Seroprevalences; Somatic Mutation; South Africa; South African; The Cancer Genome Atlas; Tissue Sample; Tissue Survival; Trypanosoma brucei brucei; Trypanosomiasis; Tumor Tissue; Vaccines; Variant; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Receptors; Virus Replication; acquired immunity; antiretroviral therapy; breast cancer survival; cancer initiation; cancer survival; carcinogenesis; cost; cytotoxic; disease natural history; gene discovery; genetic variant; genome wide association study; global health; high risk; insight; lifetime risk; lipid disorder; liver inflammation; malignant breast neoplasm; malignant stomach neoplasm; outcome forecast; pandemic disease; pathogen; prognostic value; prospective; receptor function; risk variant; transcriptome; tumor; tumor progression; tumorigenesis; viral resistance

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.

我们的重点是继续对全球健康产生巨大影响的两种传染病。人类免疫缺陷病毒（HIV）是大流行病，乙型肝炎病毒（HBV）感染和HBV相关的肝细胞癌（HCC）在东亚普遍存在，影响全球数百万人，并且无法治愈。该项目的目标是确定导致这些以及其他潜在传染病发生和发展的宿主因素。我们的目标是确定影响宿主先天限制或易感性的宿主遗传因素，这些因素在病毒病原体的获取、复制、发病机制和致癌作用中，其机制尚不完全清楚。鉴定参与病毒复制、先天免疫或获得性免疫或致癌途径的宿主蛋白将为合理开发抗病毒药物和有效疫苗提供重要见解。我们的策略是寻找对感染率或发病过程有不同影响的遗传变异，从而确定含有变异的基因是否对感染或进展有限制或易感性。我们正在使用靶向基因、全基因组关联研究（GWAS）和功能方法来发现与HIV-1、HBV感染和HBV相关肝癌相关的基因。我们还与南非和中国的研究人员建立了国际合作关系，以指导研究员，建立能力，并开展研究，解决重要的公共卫生问题（即南非的艾滋病毒和中国的hbv相关肝癌）。研究成果：1)在HIV感染的情况下，APOL1与肾脏疾病的关系。艾滋病毒阳性个体患肾脏疾病的风险增加，包括艾滋病毒相关肾病（HIVAN）、非塌陷局灶节段性肾小球硬化（FSGS）、免疫复合物肾病[以及长期接受抗逆转录病毒治疗导致的肾损伤。APOL1蛋白通过分解寄生虫，赋予对大多数形式的布鲁氏锥虫（引起锥虫病的原因）的抵抗力。APOL1基因的两个编码变异体扩展了对导致人类锥虫病的布氏体菌株的耐药性，但代价是慢性和终末期肾脏疾病的风险增加。未经治疗的艾滋病毒感染者的风险特别高（非洲裔美国人和南非人的优势比分别为29和89），其终生发展为艾滋病毒感染（一种进行性肾脏疾病）的风险为50%。随着抗逆转录病毒疗法（ART）的出现，艾滋病毒感染率有所下降，并已被接受抗逆转录病毒治疗的患者所取代，已报道了FSGS和多种形式的免疫复合物疾病。此外，据报道，缺乏持续抑制HIV复制的患者肾功能下降更快。KDIGO组织了hiv相关肾脏疾病的遗传学和基因组学以及hiv阳性个体肾脏疾病的自然史、诊断和治疗方面的国际专家小组，以确定hiv阳性个体肾脏疾病的预防和管理的最佳实践。作为艾滋病毒背景下肾脏疾病遗传学/基因组学研讨会的联合主席，我们正式确定了我们对艾滋病毒感染背景下肾脏疾病中APOL1的理解的最佳实践和知识差距。2) HBV受体NTCP基因变异与HBV感染的风险。牛磺胆酸钠共转运多肽（NTCP/SLC10A1）最近被确定为HBV的功能性细胞受体。S267F变异导致HBV受体缺失。我们评估了NTCP S267F在1000多例不同HBV感染结局（HBV抵抗、清除、慢性感染、肝硬化和HCC）患者中的相关性。S267F与HBV感染抵抗力增加（OR 0.37, p = 0.005）和肝硬化发生风险降低（OR 0.18, p = 0.01）相关，但与HCC风险无关。此外，我们通过整合和meta分析来自GEO和TCGA的8个基因表达数据集（n=1200），研究了SLC10A1在HCC肿瘤-正常组织对中的表达和预后价值。8组数据中有6组的SLC10A1在HCC肿瘤组织中的表达水平明显低于相应的正常组织（meta-p值0.0001，倍数变化1.03-9.6）。肿瘤组织中低表达与生存率低相关（Log-rank p-value0.001）。我们推测SLC10A1的降低可能导致胆汁酸的过度积累，这对肝细胞具有潜在的细胞毒性，导致肝脏炎症和再生。SLC10A1在HCC肿瘤发生中的作用，是否涉及其HBV受体功能，仍有待研究。3) APOL1风险变异与围产期HIV感染（PHIV）儿童的慢性肾脏疾病（CKD）相关。我们发现携带APOL1高危基因型的PHIV儿童和青少年患CKD的几率比携带APOL1低风险基因型的儿童和青少年高3.5倍。这项研究对撒哈拉以南非洲地区的儿童具有重要意义，那里艾滋病毒感染普遍存在，许多儿童得不到充分治疗。4)乙肝病毒与hiv感染患者非霍奇金b细胞淋巴瘤（NHL）的关系。大约3%的美国人有伯纳氏克希菌抗体，它是Q热的病原体。此前，一项对1468名法国患者的研究发现，NHL的发病率增加了25倍。艾滋病毒感染也与非霍奇金淋巴瘤有关，一些研究发现艾滋病毒感染与伯纳蒂菌较高流行率之间存在联系，但其他研究没有发现这种联系。我们假设抗伯氏c抗体在艾滋病相关非霍奇金淋巴瘤患者中的流行率更高。利用两项前瞻性HIV队列研究中储存的血浆和血清样本，我们发现在HIV感染的情况下，伯纳蒂C的血清阳性率与NHL病例的发生率或流行率无关，我们在《Blood》杂志上报道了这一结果。人类APOBEC3家族的胞苷脱氨酶（由APOBEC3 A-H基因编码）限制逆转录病毒和移动逆转录元件，但它们也可以使宿主ssDNA发生超突变。我们之前在A3-VIf通路的A3G、A3B、A3F和CUL5中发现了几个影响HIV-1感染或进展的遗传变异。A3B/A3A也被认为是癌症中的强内源性诱变剂。A3B/A3A最近被认为是多种癌症的强内源性诱变剂。例如，A3B缺失与乳腺癌风险增加有关。通过对保存在Gene Expression Omnibus （GEO）和The cancer Genome Atlas （TCGA）中的乳腺癌、肺癌和胃癌的肿瘤组织转录组和生存数据进行meta分析，我们发现几个A3基因与癌症生存相关，并且以癌症特异性的方式。A3B高表达与乳腺癌生存率较低相关，但与胃癌生存率较高相关；A3F/G高表达对胃癌生存有保护作用；A3C对乳腺癌有保护作用，但对肺癌和胃癌的预后较差。我们正在验证A3基因与胃癌的关联，并旨在验证A3基因在其他几种癌症中的变异特征。为了阐明A3B/A3A在肿瘤发生中的作用，我们利用了亚洲特有的天然A3B基因缺失多态性。通过对327例超过1000名HBV病毒慢性携带者的HCC病例进行比较，我们发现A3B缺失可能不会影响肝细胞癌（HCC）的风险。我们正在另外300个HCC组织样本中评估A3B del和A3基因表达模式对临床特征和预后的影响。