Genetics of TB resistance in HIV positive subjects

HIV 阳性受试者的结核病耐药性遗传学

• 批准号: 9511030
• 负责人: Catherine Marie Stein
• 金额: $ 58.77万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9511030
• 关键词: 5q31; ATAC-seq; Affect; Africa; Africa South of the Sahara; African; Area; Bacillus (bacterium); Bacteria; Biological; Biological Assay; Botswana; CD4 Lymphocyte Count; Candidate Disease Gene; Cause of Death; Chromatin; Clinical; Complex; Control Groups; Country; DNA; DNA Methylation; Data; Dendritic Cells; Development; Disease; Epigenetic Process; Exhibits; Functional disorder; Genes; Genetic; Genetic Variation; Genets; Genomics; Genotype; Goals; HIV; HIV Seropositivity; HIV risk; Hela Cells; High-Throughput Nucleotide Sequencing; Histones; Human; Human Genetics; IL12B gene; Immune response; Immunocompetent; Immunocompromised Host; Immunologics; Incidence; Individual; Infection; Integration Host Factors; Interleukin-12; Intervention; Knowledge; Logistic Regressions; Maps; Mediating; Methylation; Mycobacterium tuberculosis; Pathway interactions; Patients; Pattern; Phenotype; Population; Predisposition; Prospective cohort; Quantitative Trait Loci; Recruitment Activity; Regimen; Research; Research Design; Resistance; Risk; Role; Sampling; Tanzania; Technology; Testing; Time; Transposase; Tuberculin Test; Tuberculosis; Uganda; Vaccine Design; Variant; Virulent; XCL1 gene; base; bead chip; case control; cohort; cytokine; deep sequencing; density; disorder risk; epigenetic variation; epigenomics; experimental study; genetic variant; genome wide association study; innovation; insight; interest; macrophage; methylome; monocyte; novel; prevent; promoter; prospective; response; risk variant; whole genome

PROJECT SUMMARY Tuberculosis (TB) is a re-emerging disease that is highly prevalent in the developing world, especially sub-Saharan Africa. However, despite the fact that a third of humans are exposed to Myocbacterium tuberculosis (MTB) complex bacteria, most immunocompetent individuals do not progress to active TB, but remain with asymptomatic latent TB infections (LTBI). In contrast, in immunocompromised individuals with LTBI, such as those infected with the human immunodeficiency virus (HIV+), the risk of active disease is 10% and more per year, making TB the most common cause of death for HIV+ individuals living in TB endemic countries. Nonetheless, many HIV+ individuals do not progress to active disease, exhibiting a resistance phenotype. We hypothesize that HIV+ individuals exposed to MTB, but who remain disease free for several years carry genomic and/or epigenomic variants that strongly protect them from active TB. To test this we will assay patterns of genetic and epigenetic variation in two prospective African cohorts, Kampala, Uganda and Dar es Salaam, Tanzania, where HIV+ patients have been followed for over a decade. We will compare the distribution of variants in people with active TB to those who have been exposed but do not develop disease. A third cohort from the high incidence HIV regions of Botswana will also be studied using the same platforms, high density GWAS and methylome chips, and ATAC-sequencing, to assess association with TB. We will use identify candidate genes for deep re-sequencing in selected individuals with the intent of identifying functional variants. Pathways that are found to protect from active disease in highly susceptible HIV+ individuals should provide novel targets for both treatment and means to prevent disease. Lastly, we will conduct immunological experiments to examine how these genetic variants affect the immune response to TB. The knowledge gained from this study design will be important in creating TB control regimens not only in Africa, but worldwide, as it will elucidate targets of unusually large effect that have not been investigated so far.

项目摘要 结核病（TB）是一种在发展中国家高度流行的重新出现的疾病， 尤其是撒哈拉以南的非洲。然而，尽管三分之一的人类暴露在 结核分枝杆菌（MTB）复合菌，大多数免疫功能正常的个体不 进展为活动性TB，但仍为无症状潜伏性TB感染（LTBI）。而反观 免疫功能低下的LTBI个体，如感染人LTBI的那些。 免疫缺陷病毒（HIV+），活动性疾病的风险是每年10%以上，使结核病 这是结核病流行国家艾滋病毒阳性者最常见的死亡原因。 尽管如此，许多HIV+个体并没有进展为活动性疾病，表现出耐药性。 表型我们假设HIV+个体暴露于MTB，但保持无病 携带基因组和/或表观基因组变体，这些变体强烈地保护它们免受 活动性肺结核为了验证这一点，我们将在两个样本中分析遗传和表观遗传变异的模式。 乌干达坎帕拉和坦桑尼亚达累斯萨拉姆的预期非洲队列， 患者已经被跟踪了十多年。我们将比较中变体的分布 活动性结核病患者到那些接触过但没有发病的人。第三 来自博茨瓦纳艾滋病毒高发地区的队列也将使用相同的方法进行研究。 平台、高密度GWAS和甲基化组芯片以及ATAC测序，以评估 与TB有关。我们将在选定的基因组中识别候选基因进行深度重测序。 目的是识别功能变体。被发现的保护途径 从活动性疾病的高度敏感的艾滋病毒+个人应该提供新的目标， 治疗和预防疾病的方法。最后，我们将进行免疫学实验， 研究这些遗传变异如何影响对结核病的免疫反应。获得的知识 从这项研究设计将是重要的，不仅在非洲， 世界范围内，因为它将阐明目标的异常大的影响，还没有调查， 远了