GENETIC EPIDEMIOLOGY OF AIDS AND THE ROLE OF CHEMOKINE GENES

艾滋病的遗传流行病学和趋化因子基因的作用

• 批准号: 6289099
• 负责人: STEPHEN J O'BRIEN
• 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/6289099
• 关键词: AIDS; chemokine; cytogenetics; cytokine receptors; disease /disorder proneness /risk; epidemiology; genetic mapping; genetic markers; genetic polymorphism; human genetic material tag; immunogenetics; linkage mapping; molecular pathology; nucleic acid sequence; polymerase chain reaction; single strand conformation polymorphism; virus infection mechanism; virus receptors

One of the major goals of the human genome project is to understand the relationships between the genome and various phenotypes of interest. Such phenotypes include normal metabolic pressures and behavioral states, in addition to disease conditions. A number of different diseases have been shown to have a genetic basis including cancer predisposition, inborn errors of metabolism, and susceptibility to infectious agents. One infectious disease of primary interest is the acquired immunodeficiency syndrome (AIDS). Within the past several years, it has been demonstrated that the human immunodeficiency virus-1 (HIV-1) uses several chemokine receptors for cell entry. It has also been shown that the chemokine ligands (RANTES, MIP1-alpha and MIP1- beta) for the major HIV co-receptor, CCR5, can inhibit the replication of non-syncytium-forming HIV-1. Subsequent studies have revealed that mutations in several chemokines and receptors may prevent infection and/or may delay the onset of adverse clinical conditions. However, since epidemiological analyses have also shown that the known mutations in these genes do not explain all disease-related effects, a deeper appreciation of these and additional host genes is necessary for a complete understanding of the pathobiology of HIV-1. Currently about 40 distinct human chemokine genes have been identified. In the present study polymerase chain reaction (PCR) primers have been designed to encompass coding regions, transcription factor binding sites, and 5? and 3? untranslated regions for about 20 of these genes. A series of single nucleotide polymorphisms (SNPs) have been developed using the single strand conformational polymorphism (SSCP) technique and nucleotide sequence analyses. Approximately 40 SNPs have been identified to date. PCR-RFLP and Taq-Man allelic discrimination methods are being used to genotype up to 3000 clinically characterized individuals from the MACS, HGDS, ALIVE , MHCS, and SFCC HIV disease cohorts in an effort to identify genes responsible for HIV infection and/or AIDS disease progression. Results are available for analyses between clinical phenotypes and genotypes from 18 SNPs. Polymorphisms in four genes, LAG1, IL4, RANTES and MCP1, reveal an association with a clinical phenotype. Genetic Epidemiology of AIDS and the Role of Chemokine Genes - AIDS, asthma, Chemokines, Cytokines, Epidemiology, Genetic Susceptibility, linkage disequilibrium, PCR, chemokine receptors, - Human Tissues, Fluids, Cells, etc.

人类基因组计划的主要目标之一是了解基因组与各种感兴趣的表型之间的关系。除了疾病状况之外，此类表型还包括正常的代谢压力和行为状态。许多不同的疾病已被证明具有遗传基础，包括癌症易感性、先天性代谢缺陷和对传染源的易感性。人们主要关注的一种传染病是获得性免疫缺陷综合症（艾滋病）。在过去的几年中，已经证明人类免疫缺陷病毒-1 (HIV-1) 使用多种趋化因子受体进入细胞。研究还表明，主要 HIV 共受体 CCR5 的趋化因子配体（RANTES、MIP1-α 和 MIP1-β）可以抑制非合胞体形成的 HIV-1 的复制。随后的研究表明，几种趋化因子和受体的突变可以预防感染和/或延缓不良临床状况的发生。然而，由于流行病学分析还表明，这些基因中的已知突变并不能解释所有与疾病相关的影响，因此有必要对这些和其他宿主基因进行更深入的了解，以全面了解 HIV-1 的病理学。目前已鉴定出约 40 种不同的人类趋化因子基因。在本研究中，聚合酶链反应（PCR）引物被设计为包含编码区、转录因子结合位点和5？和3？其中大约 20 个基因的非翻译区。使用单链构象多态性（SSCP）技术和核苷酸序列分析开发了一系列单核苷酸多态性（SNP）。迄今为止，已鉴定出大约 40 个 SNP。 PCR-RFLP 和 Taq-Man 等位基因区分方法用于对来自 MACS、HGDS、ALIVE、MHCS 和 SFCC HIV 疾病队列的多达 3000 名具有临床特征的个体进行基因分型，以鉴定导致 HIV 感染和/或 AIDS 的基因疾病进展。结果可用于 18 个 SNP 的临床表型和基因型之间的分析。 LAG1、IL4、RANTES 和 MCP1 四个基因的多态性揭示了与临床表型的关联。艾滋病的遗传流行病学和趋化因子基因的作用 - 艾滋病、哮喘、趋化因子、细胞因子、流行病学、遗传易感性、连锁不平衡、PCR、趋化因子受体、 - 人体组织、体液、细胞等。