Candidate Gene Polymorphisms Associated with Infect. Dis

与感染相关的候选基因多态性。

• 批准号: 7049814
• 负责人: CHERYL ANN WINKLER
• 金额: --
• 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/7049814
• 关键词: AIDS; Epstein Barr virus; HIV infections; cell line; clinical research; epidemiology; gene environment interaction; genetic mapping; genetic polymorphism; genetic screening; genetic susceptibility; hepatitis B virus group; hepatitis C virus; hepatocellular carcinoma; high throughput technology; human genetic material tag; human immunodeficiency virus 1; human population genetics; human tissue; infection related neoplasm /cancer; nasopharyngeal neoplasms; pathologic process; virus diseases; virus genetics; virus infection mechanism; virus related neoplasm /cancer

Infectious diseases, in addition to causing acute and sometimes chronic infections, are also a leading cause of many common cancers including gastric cancer, cervical cancer, hepatocellular carcinoma, nasal pharyngeal carcinoma (NPC), Epstein Barr virus (EBV), and lymphoma. However, the role of host genetic factors in host resistance, chronic infection and pathogenesis leading to disease and/or malignancies is not well understood. Variation in genes encoding proteins providing acquired and innate immunity, proteins required for the completion of the viral life cycle, and tumor suppressors may affect individual susceptibility to the initial infection and the outcome of chronic infection. The investigation of host genetic factors that modify HIV-1 and Hepatitis C virus (HCV) infection and disease progression or that may predispose to NPC or heptocellular carcinoma may lead to better understanding of host resistance and pathogenesis in response to common pathogens and may lead to targeted therapeutic interventions. The cytodine deaminase, APOBEC3G, belonging to the APOBEC RNA-editing enzyme family, blocks HIV-1 replication by inducing G to A hypermutation in newly synthesized viral DNA; however, this suppression is blocked by HIV-1 virion infectivity factor (Vif). After HIV-1 Vif forms a complex with the host protein Cul5, it binds to APOBEC3G preventing the encapsulation of APOBEC3G in the newly formed virion. Wildtype HIV-1 is able to replicate in the presence of APOBEC3G whereas HIV-1 Vif strains cannot. We tested the hypothesis that genetic variants of the APOBEC3G gene may affect HIV-1 transmission and disease progression in 5 HIV-1 natural cohorts. Single nucleotide polymorphisms (SNPs) were screened in the 5'-untranslated region, 8 exons, exon-intron junctions, and 3'-untranslated region and seven SNPs were identified. The homozygous variant allele of H186R, a nonsynonymous change in exon 4 present only in African Americans, was associated with accelerated rate of progression to AIDS and death in African Americans. Two haplotypes carrying the variant allele of 199376G/C, located in intron 4, were also modestly associated with accelerated disease progression, separately in European- and African-Americans. The results suggest that APOBEC3G may play a role in the genetic modulation of HIV-1 disease. The functional basis for these associations is under investigation. APOBEG3C is a very strong candidate as a target for therapeutic intervention. We are now examining the evolution of APOBEC family members and determining if other family members such as APOBEC RNA editing enzyme are involved in HIV-1 diseases or associated neoplasms. We are now investigating the role of RNA editing enzymes in AIDS-related lymphoma. HIV-1 associated non-Hodgkin's lymphoma (NHL) is characterized by oncogenic changes in B cell DNA, induced by activation-induced cytidine deaminase (AICDA). The ability of HIV-1 Vif to suppress antiviral activity of APOBEC3G is specifically dependent on Cul5-SCF function, allowing Vif to interact with APOBEC3G and induce its ubiquitination and degradation. Thus, the Cul5-SCF pathway used by Vif may determine the differential viral activity conferred by APOBEC3G. We have genotyped 9 SNPs in Cul5 in the AIDS cohort. Four SNPs showed significant association with AIDS progression to CD4 200 and AIDS 93 in African Americans. These results suggest that Cul5 variant alleles may retard HIV-1 CD4 T cell depletion but do not block infection or prevent AIDS. Tripartite motif-containing 5 (TRIM5) is a protein that blocks HIV-1 infection of rhesus monkeys by binding to the capsid of the HIV-1 virion shortly after cell-entry. The viral genome is therefore not reverse-transcribed or integrated into the host genome. We have characterized the extent of genetic variation in the human TRIM5 gene and in a collaborative study investigated the genomic structure and phylogenetic relationships of primate TRIM5 genes. Interestingly, the gene is highly variant with an excess of codon-changing sites suggesting that this gene may be under selection for amino acid diversity. In addition, the extent of linkage equilibrium among intragenic SNPs and the haplotype structure of the gene both suggest that this gene may be under balancing selection and that a number of different TRIM5 genes provides selective advantage. We are now investigating the consequences of genetic variants on HIV-1 infection and progression to AIDS-defining conditions as well as on viral load and the trajectory of CD4 cell loss. These studies point to a role for innate immunity by TRIM5 against infection in human infectious disease. The use of haplotype tagging SNPs (htSNP) to identify hyplotype blocks in the human genome associated with disease is a key goal of the current hapmap project. However, the extensive disequilibrium within a haplotype block potentially confounds the concluding step of association analysis to identify specific polymorphism with a potential functional role in disease. The cluster of chemokine receptor genes surrounding CCR5 inChromosome 3p21 contains several known and potential functional genes affecting HIV-1/AIDS in a complex pattern of disequilibrium. A bootstrap-replicated multivariate survival analysis on six polymorphisms typed in five HIV-1/AIDS cohorts revealed a strong recessive association of a non-conservative amino acid change in CCRL2 (Y167F) with protection against AIDS, attributable to a specific protection against Pneumocystiscarinii pneumonia (PCP). Future plans are to investigate the role of CCRL2 in simian immunodeficiency virus (SIV)-infected macaques in a collaborative investigation. Significant progress has been made in the study investigating the role of EBV-associated NPC. We have recruited more than 400 NPC cases, their unaffected spouses who serve as a control, plus a parent or child for haplotype inference. A second case-control study to investigate the role of EBV persistence as determined by the presence of IgA antibody to viral capsid antigen (VCA) has also been established. The presence of this antibody is a significant risk factor for the development of NPC. We determined genotypes for 319 alleles in 34 microsatellite markers in the 18 Mb NPC-associated region. This regional fine mapping study suggests that the Chr 4 region may harbor genes associated with EBV persistence, a necessary prerequisite for NPV development.

传染病除了引起急性和有时慢性感染外，还是许多常见癌症的主要原因，包括胃癌、宫颈癌、肝细胞癌、鼻咽癌 (NPC)、EB 病毒 (EBV) 和淋巴瘤。然而，宿主遗传因素在宿主抵抗、慢性感染以及导致疾病和/或恶性肿瘤的发病机制中的作用尚不清楚。编码提供获得性和先天免疫的蛋白质、完成病毒生命周期所需的蛋白质和肿瘤抑制因子的基因的变异可能会影响个体对初始感染的易感性和慢性感染的结果。对改变 HIV-1 和丙型肝炎病毒 (HCV) 感染和疾病进展或可能诱发鼻咽癌或肝细胞癌的宿主遗传因素的研究可能有助于更好地了解宿主对常见病原体的抵抗力和发病机制，并可能导致有针对性的治疗干预。 胞嘧啶脱氨酶 APOBEC3G 属于 APOBEC RNA 编辑酶家族，通过在新合成的病毒 DNA 中诱导 G 到 A 的超突变来阻止 HIV-1 复制；然而，这种抑制会被 HIV-1 病毒颗粒感染因子 (Vif) 阻断。 HIV-1 Vif 与宿主蛋白 Cul5 形成复合物后，它与 APOBEC3G 结合，防止 APOBEC3G 封装在新形成的病毒粒子中。野生型 HIV-1 能够在 APOBEC3G 存在的情况下复制，而 HIV-1 Vif 株则不能。我们在 5 个 HIV-1 自然队列中测试了 APOBEC3G 基因的遗传变异可能影响 HIV-1 传播和疾病进展的假设。在5'-非翻译区、8个外显子、外显子-内含子连接和3'-非翻译区中筛选单核苷酸多态性(SNP)，并鉴定出7个SNP。 H186R 的纯合变异等位基因是仅在非裔美国人中存在的外显子 4 的非同义变化，与非裔美国人的艾滋病进展速度加快和死亡有关。携带位于内含子 4 中的 199376G/C 变异等位基因的两种单倍型也与疾病进展加速相关，分别在欧洲人和非洲裔美国人中。结果表明 APOBEC3G 可能在 HIV-1 疾病的遗传调节中发挥作用。这些协会的功能基础正在调查中。 APOBEG3C 是非常有力的候选治疗干预靶标。 我们现在正在研究 APOBEC 家族成员的进化，并确定其他家族成员（例如 APOBEC RNA 编辑酶）是否与 HIV-1 疾病或相关肿瘤有关。我们现在正在研究 RNA 编辑酶在艾滋病相关淋巴瘤中的作用。 HIV-1 相关非霍奇金淋巴瘤 (NHL) 的特点是 B 细胞 DNA 发生致癌变化，由激活诱导胞苷脱氨酶 (AICDA) 诱导。 HIV-1 Vif 抑制 APOBEC3G 抗病毒活性的能力特别依赖于 Cul5-SCF 功能，使 Vif 能够与 APOBEC3G 相互作用并诱导其泛素化和降解。因此，Vif 使用的 Cul5-SCF 途径可能决定 APOBEC3G 赋予的病毒活性差异。我们对 AIDS 队列中的 Cul5 中的 9 个 SNP 进行了基因分型。四个 SNP 显示与非裔美国人中 AIDS 进展为 CD4 200 和 AIDS 93 显着相关。这些结果表明，Cul5 变异等位基因可能会延缓 HIV-1 CD4 T 细胞的消耗，但不会阻止感染或预防艾滋病。 含三联基序 5 (TRIM5) 是一种蛋白质，可在进入细胞后不久与 HIV-1 病毒体的衣壳结合，从而阻止恒河猴的 HIV-1 感染。因此，病毒基因组不会逆转录或整合到宿主基因组中。我们描述了人类 TRIM5 基因的遗传变异程度，并在一项合作研究中调查了灵长类 TRIM5 基因的基因组结构和系统发育关系。有趣的是，该基因具有高度变异性，具有过量的密码子改变位点，表明该基因可能因氨基酸多样性而受到选择。此外，基因内SNP之间的连锁平衡程度和基因的单倍型结构都表明该基因可能处于平衡选择之下，并且许多不同的TRIM5基因提供了选择优势。我们现在正在研究遗传变异对 HIV-1 感染和进展为艾滋病定义条件的影响，以及对病毒载量和 CD4 细胞损失轨迹的影响。这些研究指出了 TRIM5 对人类传染病感染的先天免疫的作用。 使用单倍型标记单核苷酸多态性 (htSNP) 来识别人类基因组中与疾病相关的亚型型块是当前单倍型图项目的一个关键目标。然而，单倍型块内的广泛不平衡可能会混淆关联分析的结论步骤，以识别在疾病中具有潜在功能作用的特定多态性。 3p21 染色体中 CCR5 周围的趋化因子受体基因簇包含几个已知的和潜在的功能基因，以复杂的不平衡模式影响 HIV-1/AIDS。对五个 HIV-1/AIDS 队列中的 6 个多态性进行的引导复制多变量生存分析显示，CCRL2 (Y167F) 中的非保守氨基酸变化与预防 AIDS 之间存在很强的隐性关联，这归因于对卡氏肺囊虫肺炎 (PCP) 的特异性保护。未来的计划是通过合作研究 CCRL2 在感染猿猴免疫缺陷病毒 (SIV) 的猕猴中的作用。 调查 EBV 相关 NPC 作用的研究已取得重大进展。我们招募了 400 多个鼻咽癌病例，将其未受影响的配偶作为对照，加上父母或孩子进行单倍型推断。第二项病例对照研究也已建立，旨在调查 EBV 持久性的作用，该作用是通过病毒衣壳抗原 (VCA) 的 IgA 抗体的存在来确定的。这种抗体的存在是鼻咽癌发生的一个重要危险因素。我们确定了 18 Mb NPC 相关区域中 34 个微卫星标记的 319 个等位基因的基因型。这项区域精细绘图研究表明，Chr 4 区域可能含有与 EBV 持久性相关的基因，这是 NPV 发展的必要先决条件。