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）是一种重新出现的疾病，在发展中国家中非常普遍， 特别是撒哈拉以南非洲。但是，尽管有三分之一的人暴露于 心肌细菌结核病（MTB）复合细菌，大多数免疫能力的个体没有 进展到活跃的结核病，但留下无症状的潜在结核病感染（LTBI）。相反，在 具有LTBI的免疫功能低下的个体，例如感染了人类的人 免疫缺陷病毒（HIV+），活动疾病的风险每年为10％或更高，使结核病 居住在结核病地区的艾滋病毒+个体的最常见死亡原因。 尽管如此，许多HIV+个体并未发展为活性疾病，表现出阻力 表型。我们假设艾滋病毒+个体暴露于MTB，但仍然无病 几年来，具有强烈保护它们免受的基因组和/或表观基因组变体 活性结核为了测试这一点，我们将分析两个遗传和表观遗传变异的模式 坦桑尼亚的坎帕拉，乌干达和达累斯萨拉姆的潜在非洲同伙，艾滋病毒+ 患者已经遵循了十多年。我们将比较变体的分布 有活跃的结核病的人对那些暴露但不发展疾病的人。第三 还将使用相同 平台，高密度GWAS和甲基组芯片，以及ATAC的测序，以评估 与结核病的关联。我们将使用识别候选基因进行精选的深入重新测试 具有识别功能变体的意图的个体。发现可以保护的途径 来自高度易感HIV+个体的活动疾病应为这两者提供新的目标 治疗和预防疾病的方法。最后，我们将进行免疫实验 检查这些遗传变异如何影响对结核病的免疫反应。知识获得了 从这项研究设计中，不仅在非洲创建结核病控制方案非常重要，而且 在全球范围 远的。