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.

我们的重点是两种继续对全球健康产生巨大影响的传染病。人类免疫缺陷病毒 (HIV) 正在流行，乙型肝炎病毒 (HBV) 感染和 HBV 相关肝细胞癌 (HCC) 在东亚流行，影响全球数百万人，且无法治愈。该项目的目标是确定导致这些以及潜在的其他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，这些因素包括病毒病原体的获得、复制和发病机制以及致癌作用，其机制尚不完全清楚。鉴定参与病毒复制、先天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机制进程产生不同影响的遗传变异，从而识别出含有变异的基因，从而赋予对感染或进展的限制或易感性。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，以指导研究员、建设能力并开展研究，以解决重要的公共卫生问题（即南非的艾滋病毒和中国的乙型肝炎相关肝癌）。成就：1) APOL1 与 HIV 感染情况下的肾脏疾病相关。 HIV 阳性个体患肾脏疾病的风险增加，包括 HIV 相关肾病 (HIVAN)、非塌陷性局灶节段性肾小球硬化症 (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 蛋白通过裂解寄生虫，赋予对大多数布氏锥虫（锥虫病的病因）的抵抗力。 APOL1 基因中的两个编码变异增强了对引起人类锥虫病的布氏锥虫菌株的抵抗力，但代价是增加了慢性和终末期肾病的风险。对于未经治疗的 HIV 感染者（非裔美国人和南非人的比值比分别为 29 和 89）来说，这种风险尤其高，他们终生患 HIVAN（一种进行性肾病）的风险为 50%。随着抗逆转录病毒疗法 (ART) 的出现，HIVAN 患病率已经下降，并已被接受 ART 治疗的患者所取代，据报道，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速度更快。）一个由 HIV 相关肾病遗传学和基因组学以及肾病自然史、诊断和治疗方面的国际专家组成的小组KDIGO 组织了 HIV 阳性个体肾脏疾病的组织，以确定预防和管理 HIV 阳性个体肾脏疾病的最佳实践。作为 HIV 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 HIV 感染背景下肾脏疾病中 APOL1 的理解的最佳实践和知识差距，以供发表。 2) HBV受体NTCP基因变异与HBV感染风险。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 受体丧失。我们评估了 1000 多名具有不同 HBV 感染结果的患者中 NTCP S267F 的关联：HBV 耐药、清除、慢性感染、肝硬化和 HCC。 S267F 与 HBV 感染抵抗力增加（OR 0.37，p = 0.005）和肝硬化发展风险降低（OR 0.18，P = 0.01）相关，但与 HCC 风险无关。此外，我们正在通过整合和荟萃分析来自 GEO 和 TCGA 数据集的八个基因表达数据集（n = 1200）来研究 HCC 肿瘤-正常组织对中 SLC10A1 的表达和预后价值。在8个数据集中的6个数据集中，与相应的正常组织相比，SLC10A1在HCC肿瘤组织中的表达水平显着降低（元p值0.0001，倍数变化1.03-9.6）。肿瘤组织中的低表达与较差的生存率相关（Log-rank p-value0.001）。我们假设 SLC10A1 减少可能导致胆汁酸过度积累，胆汁酸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，仍有待探讨。 3) APOL1 风险变异与围产期 HIV 感染 (PHIV) 儿童的慢性肾病 (CKD) 相关。我们发现，携带 APOL1 高风险基因型的 PHIV 儿童和青少年患 CKD 的几率是携带 APOL1 低风险基因型的儿童和青少年的 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，那里的艾滋病毒感染很普遍，而且许多儿童没有得到充分的治疗。 4) 伯内特柯克斯体病毒与 HIV 感染者中的非霍奇金 B 细胞淋巴瘤 (NHL) 的关联。大约 3% 的美国人拥有伯氏柯克斯体抗体，伯氏柯克斯体是 Q 热的病原体。此前，一项针对 1468 名法国患者的研究发现 NHL 增加了 25 倍）。 HIV 感染也与 NHL 相关，并且在一些研究中发现了 HIV 感染与伯内特念珠菌较高患病率之间的联系，但在其他研究中尚未发现。我们假设艾滋病相关 NHL 患者中抗伯内特衣原体抗体的患病率会更高。使用来自两项前瞻性 HIV 队列研究的储存血浆和血清样本，我们发现伯内特念珠菌血清流行率与 HIV 感染环境中的事件或流行 NHL 病例无关，我们在《血液》杂志上对此进行了报道。 5) APOBEC3基因对癌症发生和进展的影响。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因子，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 也被认为是癌症中强内源性诱变剂。 A3B/A3A 最近被认为是多种癌症中强内源性诱变剂。例如，A3B 缺失与乳腺癌风险升高相关。通过对基因表达综合库（GEO）和癌症基因组图谱（TCGA）中的癌症组织转录组和乳腺癌、肺癌和胃癌的生存数据进行荟萃分析，我们发现几个A3基因与癌症生存相关，在癌症特定方式。高 A3B 表达与乳腺癌生存率较差相关，但胃癌生存率较高；高 A3F/G 表达对胃癌存活具有保护作用； A3C 显示出对乳腺癌的保护作用，但它与肺癌和胃癌的较差结果相关。我们正在验证 A3 基因与胃癌的关联，并旨在验证其他几种癌症中的 A3 基因变异特征。为了阐明 A3B/A3A 在肿瘤发生中的作用，我们利用亚洲特有的天然 A3B 基因缺失多态性。通过比较 327 例 HCC 病例与 1000 多名 HBV 病毒慢性携带者，我们发现 A3B 缺失可能不会影响肝细胞癌 (HCC) 的风险。我们正在评估另外 300 个 HCC 组织样本中 A3B del 和 A3 基因表达的模式，以了解它们对临床特征和预后的影响。