Human Genetics of Tuberculosis

结核病的人类遗传学

基本信息

批准号：
10268806
负责人：
Jean-Laurent Casanova
金额：
$ 51.51万
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/10268806
关键词：
Accounting Affect African Alleles Alveolar Macrophages Asians Biochemical Candidate Disease Gene Cell Line Cells Clinical Code Collaborations Collection Complementary DNA Computer Analysis Computing Methodologies Cytometry Data Databases Development Disease 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 Interferons Interleukin-12 Investigation Knowledge Leukocytes Loss of Heterozygosity Minority Modeling Molecular Mycobacterium tuberculosis Pathogenesis Pathway interactions Patient Recruitments Patients Penetrance Pharmacology Population Population Heterogeneity Predisposition Preventive Primary Infection Production Proteins Proxy Recurrence Relapse Reporting Risk Role Sampling Siblings TNF gene TYK2 Techniques Technology Testing Therapeutic Tuberculosis Variant base candidate identification causal variant cell type exome sequencing experimental study genetic variant genome sequencing genome wide association study genome-wide high dimensionality immunopathology induced pluripotent stem cell interleukin-23 kindred loss of function macrophage 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.

项目概要由结核分枝杆菌 (Mtb) 引起的结核病 (TB) 是大约四分之一的主要健康问题。世界人口受到感染，但只有少数人在原发感染期间或后来感染期间发展为结核病继发感染或潜伏结核分枝杆菌的重新激活遗传流行病学证据强烈表明结核病是自 2000 年起，我们就对其分子基础进行了剖析。我们发现了 2 个因素。导致结核病的先天性免疫缺陷 (IEI) 类型，均会损害干扰素 (IFN)-γ 免疫力：(i) 罕见的 IEI，例如在少数结核病患者中发现的常染色体隐性遗传性完全性 IL-12Rβ1 和 TYK2 缺陷，以及 (ii) 由于 TYK2 错义 P1104A 变体的纯合性，选择性破坏 IL-23-，导致常见 IEI 依赖 IFN-γ 免疫，占欧洲结核病病例的 1% 这些发现提供了证据。在特定种族中，人类结核病存在罕见和常见的单基因原理，并且确定 TYK2 依赖性 IFN-γ 的产生对于 Mtb 的保护性免疫至关重要。大多数结核病患者缺乏遗传病因，我们认为结核病是多样性集合的结果。单基因或双基因 IEI，具有不完全或更罕见的完全外显率，并且比例相当大为了发现这些变异，我们的项目将结合一个候选基因。该方法专注于罕见和常见的编码 TYK2 变异，并在全基因组范围内搜索罕见和常见的变异其他基因变异的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之前在海地和世界各地招募的结核病患者（> 1,500 名），遵循以下组合策略：(i) 基于下一代测序的综合遗传研究（>900 已提供全外显子组测序数据的样本），以使用以下方法搜索候选结核病致病变异不同遗传假设（遗传异质性或同质性，单基因或双基因遗传），以及（ii）深入的功能研究以对蛋白质进行生化表征由新发现的候选变体编码，并在免疫学上验证它们的因果作用我们还将测试这些 IEI 的效果是否可能受到 Mtb 菌株的影响。我们对海地患者进行的特定宿主-病原体相互作用研究表明，这一点。该方法是富有成效的，因为我们已经确定了强大的候选基因型，包括双等位基因功能丧失 TYK2、TNF、BTN2A2 和 PDCD1 的罕见变异，以及 IL10RA 和 IL10RA 的单或双等位基因常见变异我们寻找控制单基因或双基因 IEI 的罕见和常见变异。高外显率结核病的发展将破译人类对结核分枝杆菌的保护性免疫机制。这种方法也将为新的预防或治疗方法铺平道路，旨在拯救基因有结核病风险或患有结核病的患者免疫反应不足。