Human Genetics of Tuberculosis

结核病的人类遗传学

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要结核分枝杆菌（MTB）引起的结核病（TB）是一个主要的健康问题。大约四分之一世界人口被感染，但在初次感染期间或之后，只有少数族裔发展潜在MTB的继发感染或重新激活。遗传流行病学证据强烈表明结核病是由人类遗传易感性驱动。自2000年以来就已经解剖了它的分子基础。我们发现了2 原子质的先天性错误（IEI）的类型，均损害干扰素（IFN）-γ免疫学：（i）罕见的IEI，例如，在一些结核病患者中发现的常染色体隐性完整IL-12Rβ1和TYK2缺陷，以及（ii）A 由于TYK2错义P1104A变体的纯合性引起的常见IEI，它有选择地破坏IL-23-- 依赖性IFN-γ免疫，占欧洲结核病病例的1％。这些发现提供了证明原则是，在特定种族和确定TYK2依赖性IFN-γ的产生对于对MTB的保护性免疫至关重要。但是，差距大多数结核病患者缺乏遗传病因。我们假设结核病是潜水员收藏的结果单基因或二元性IEI，不完整或更少完全完整的渗透率，并且比例很大潜水祖先的人群。要发现这些变体，我们的项目将结合一个候选基因侧重于稀有和常见的编码TYK2变体，全基因组搜索稀有和常见其他基因中的变体。结核病患者将在海地招募，特别关注属于家庭的患者至少有两个受结核病影响的兄弟姐妹和/或复发形式的结核病，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全球招募的结核病患者（> 1,500），遵循结合策略：（i）基于下一代测序的全面遗传研究（> 900 具有整个外显子测序数据的样本）已经可用）搜索使用候选TB的变体在不同遗传假设（遗传异质性或同质性，单基因或二元性遗传）和（ii）深入的功能研究以生化为特征蛋白质由新发现的候选变体编码，并在分子和细胞水平。我们还将测试这些IEI的影响是否可能受MTB菌株的影响使用海地患者的特定宿主病原体相互作用研究。我们的初步数据表明这方法是富有成果的，因为我们已经确定了强大的候选基因型，包括双 - 平衡功能丧失 TYK2，TNF，BTN2A2和PDCD1以及IL10RA和单相的共同变化的罕见变化 HLA-DRB1。我们搜索控制单基或二元的稀有和常见变体IEI 具有较高渗透率的结核病的发展将使人类对MTB的免疫力破译。这种方法还将为新的预防或治疗方法铺平道路，旨在普遍营救患有或结核病的患者的免疫调查不足。