Human Genetics of Tuberculosis

结核病的人类遗传学

• 批准号: 10621305
• 负责人: Jean-Laurent Casanova
• 金额: $ 44.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621305
• 关键词: Accounting; Affect; African; Alleles; Alveolar Macrophages; Biochemical; Candidate Disease Gene; Cell Line; Cells; Clinical; Code; Collaborations; Collection; Complementary DNA; Computer Analysis; Computing Methodologies; Cytometry; Data; Databases; Development; Disease; Dryness; East Asian; Epidemiology; Ethnic Origin; Etiology; European; Exposure to; Family; Fibroblasts; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Genotype; HLA-DRB1; Haiti; Haitian; Health; Hereditary Disease; Human; Human Genetics; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunophenotyping; Impairment; In Vitro; Individual; Infection; Interferon Type II; Interleukin-12; Investigation; Knowledge; Leukocytes; Loss of Heterozygosity; Macrophage; Minority; Minority Groups; Modeling; Molecular; Mycobacterium tuberculosis; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Penetrance; Pharmacology; Population; Population Heterogeneity; Predisposition; Preventive; Primary Infection; Probability; Production; Proteins; Proxy; Recurrence; Relapse; Reporting; Risk; Role; Sampling; Siblings; TNF gene; TYK2; Techniques; Technology; Testing; Therapeutic; Tuberculosis; Variant; autosome; candidate identification; causal variant; cell type; exome sequencing; experimental study; genetic epidemiology; genetic variant; genome sequencing; genome wide association study; genome-wide; high dimensionality; immunopathology; induced pluripotent stem cell; interleukin-23; kindred; loss of function; mouse model; next generation sequencing; novel; pathogen; reactivation from latency; recruit; response; secondary infection; software development; stem; transcriptome sequencing; whole genome

Project Summary Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a major health problem. About a quarter of the world population is infected, yet only a minority develop TB, either during primary infection, or later during secondary infection or reactivation of latent Mtb. Genetic epidemiological evidence strongly suggests that TB is driven by human genetic predisposition. Its molecular basis has been dissected since 2000. We discovered 2 types of inborn errors of immunity (IEI) underlying TB, both impairing interferon (IFN)-γ immunity: (i) rare IEI, such as autosomal recessive complete IL-12Rβ1 and TYK2 deficiencies, found in a few TB patients, and (ii) a common IEI due to homozygosity for the TYK2 missense P1104A variant that selectively disrupts IL-23- dependent IFN-γ immunity, accounting for up to 1% of European TB cases. These findings provided proof of principle that there are both rare and common monogenic etiologies of human TB, in specific ethnicities, and established that TYK2-dependent IFN-γ production is essential for protective immunity to Mtb. However, the vast majority of TB patients lack a genetic etiology. We hypothesize that TB is the consequence of a diverse collection of monogenic or digenic IEI, with incomplete or more rarely complete penetrance, and in a sizeable proportion of populations of diverse ancestries. To discover these variants, our project will combine a candidate gene approach focused on rare and common coding TYK2 variants with a genome-wide search for rare and common variants in other genes. TB patients will be recruited in Haiti with a specific focus on patients belonging to families with at least two TB-affected siblings, and/or with recurrent forms of TB, as these patients are more likely to carry IEI. Our project will also take advantage of our previously recruited TB patients in Haiti and worldwide (>1,500), following a strategy combining: (i) a comprehensive genetic study based on next generation sequencing (>900 samples with whole exome sequencing data already available) to search for candidate TB-causing variants using cutting-edge computational analyses under different genetic hypotheses (genetic heterogeneity or homogeneity, monogenic or digenic inheritance), and (ii) in-depth functional studies to biochemically characterize the proteins encoded by the newly discovered candidate variants, and to validate their causal role immunologically at the molecular and cellular levels. We will also test whether the effects of these IEI may be influenced by Mtb strains using a specific host-pathogen interaction study in Haitian patients. Our preliminary data indicate that this approach is fruitful, as we already identified strong candidate genotypes, including both bi-allelic loss-of-function rare variations in TYK2, TNF, BTN2A2, and PDCD1, and mono- or bi-allelic common variations in IL10RA and HLA-DRB1. Our search for rare and common variants underlying monogenic or digenic IEI that govern the development of TB with high penetrance will decipher mechanisms of protective immunity to Mtb in humans. This approach will also pave the way to new preventive or therapeutic approaches, aiming to rescue genetically deficient immune responses in patients at risk of, or with TB.

项目摘要 由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）是一个严重的健康问题。约四分之一 世界人口受到感染，但只有少数人在初次感染期间或以后感染期间发展为结核病。 继发感染或潜伏Mtb的再激活。遗传流行病学证据有力地表明，结核病是 是由人类的遗传倾向驱动的自2000年以来，其分子基础已经被解剖。我们发现2 TB潜在的先天性免疫缺陷（IEI）类型，均损害干扰素（IFN）-γ免疫力：（i）罕见IEI， 如常染色体隐性完全IL-12 R β1和TYK 2缺陷，在少数TB患者中发现，和（ii） 由于TYK 2错义P1104 A变异体的纯合性导致的常见IEI，该变异体选择性破坏IL-23- 依赖IFN-γ的免疫，占欧洲结核病病例的1%。这些发现证明， 在特定种族中，存在罕见和常见的人类结核病单基因病因的原则，以及 确定TYK 2依赖性IFN-γ产生对于针对Mtb的保护性免疫是必需的。但绝 大多数结核病患者缺乏遗传病因。我们假设结核病是多种多样的收集的结果 单基因或双基因IEI，不完全或更罕见的完全突变，并且在相当大的比例中 不同祖先的人口。为了发现这些变异，我们的项目将联合收割机结合一个候选基因 一种方法专注于罕见和常见的TYK 2编码变体，并在全基因组范围内搜索罕见和常见的TYK 2编码变体。 其他基因的变异。将在海地招募结核病患者，特别关注家庭成员患者 至少有两个受结核病影响的兄弟姐妹，和/或患有复发性结核病，因为这些患者更有可能携带 IEI我们的项目还将利用我们以前在海地和世界各地招募的结核病患者（> 1，500）， （i）基于下一代测序的综合遗传研究（>900 具有全外显子组测序数据的样本），以使用 在不同的遗传假设（遗传异质性或同质性， 单基因或双基因遗传），以及（ii）深入的功能研究，以生物化学表征蛋白质 编码的新发现的候选变异，并验证其因果作用免疫学在 分子和细胞水平。我们还将测试这些IEI的效果是否会受到Mtb菌株的影响 在海地患者中使用特定宿主-病原体相互作用研究。我们的初步数据表明，这 这种方法是富有成效的，因为我们已经确定了强有力的候选基因型，包括双等位基因功能丧失， TYK 2、TNF、BTN 2A 2和PDCD 1的罕见变异，以及IL 10 RA和PDCD 1的单或双等位基因常见变异。 HLA-DRB1。我们寻找罕见的和常见的变异基础单基因或双基因IEI，控制 具有高耐药率的TB的发展将解释人类对Mtb的保护性免疫机制。 这种方法还将为新的预防或治疗方法铺平道路，旨在从遗传学上挽救 有结核病风险或患有结核病的患者的免疫反应缺陷。