Human Genetic risk factors for Disseminated Coccidioidomycosis (DCM)

播散性球孢子菌病 (DCM) 的人类遗传危险因素

• 批准号: 10554385
• 负责人: Valerie A Arboleda
• 金额: $ 13.48万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554385
• 关键词: ATAC-seq; Acute Lymphocytic Leukemia; African American; African American population; Asthma; Biological Models; Blood; Chromatin; Clinical; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Code; DNA; Data; Data Analyses; Data Set; Defect; Diagnosis; Disease; Eczema; Environment; Epigenetic Process; Ethnic Origin; Ethnic Population; European ancestry; Genes; Genetic; Genetic Markers; Genetic Models; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Human; Human Genetics; Immune; Immune Response Genes; Immune signaling; Immunogenetics; In Vitro; Individual; Infection; Inherited; Latino; Lung infections; Malignant Neoplasms; Molecular; Morbidity - disease rate; Mus; Mutation; Natural Immunity; North America; Observational epidemiology; Pathogenesis; Pathogenicity; Pathway interactions; Patient Self-Report; Patients; Persons; Population; Population Group; Primary Infection; Proteins; Publishing; RNA; RNA Splicing; Race; Regulation; Regulator Genes; Regulatory Pathway; Risk; Risk Factors; Role; Sample Size; Severities; Signal Pathway; Signal Transduction; Source; Transcriptional Regulation; Untranslated RNA; Validation; Variant; Virulence; adaptive immunity; desert fever; epidemiology study; exome sequencing; functional genomics; genetic risk factor; genetic variant; genome sequencing; genome-wide; genomic data; genomic tools; high risk; immunomodulatory therapies; insight; mortality; mouse genetics; multiple omics; novel; racial population; rare variant; risk variant; sex; single-cell RNA sequencing; sociodemographics; software development; terabyte; transcriptome; transcriptome sequencing; transcriptomics

Scientific Project 3: Human Genetic Risk Factors for Disseminated Coccidioidomycosis (DCM) ABSTRACT This project will focus on elucidating human host genetic risk variants that predispose individuals to DCM. For the past 80 years, epidemiological studies have demonstrated that certain specific racial and ethnic groups were more likely to progress towards severe disseminated Coccidioidomycosis, While many of these observations have held up over, the underlying mechanistic and genetic pathogenesis underlying these epidemiological observation have not been fully evaluated. There have been several major barriers to these types of genomic studies where the relationship between host-genetic background and environment (here infection): 1) small- sample sizes for most studies; 2) challenge of handling terabytes of genomic data; 3) limited sequencing data for non-european populations;and 4) identifying relevant functional readouts to confirm the effect of variants in relevant model systems. In this U19 proposal, project 3 brings together over 600 existing exome and genome sequencing datasets and proposes to collect and sequence over 500 additional cases and controls. This will be the largest genetic study of coccidioidomycosis to date. Key to this data analysis is the experts in this proposal whose expertise enables us to handle Terabytes of data and to analyze it using ancestry-specific approaches. We will explore two major hypotheses: that common variants that make up ancestry-specific approaches underly race and ethnicity specific differences in DCM or that rare genetic variants in key immune signaling pathways increase risk of DCM. Both hypotheses are not necessarily mutually exclusive and may explain some of the disease associations that have been observed. In addition to identifying the DNA variants, we will perform ATAC-seq, RNA-sequencing studies to functionally validate non-coding and splicing changes caused by non- coding genetic variants. A key aspect of this project is its ability to rapidly integrate with projects 1 and 2 and Core C in order to validate novel genetic variants and their effects on immune pathways. It will allow us to directly bridge the gap between identified genetic variants and clinical function.

科学项目3：传播球菌病的人类遗传危险因素（DCM） 抽象的 该项目将着重于阐明使个人易受DCM的人类宿主遗传风险变异。为了 在过去的80年中，流行病学研究表明，某些特定的种族和种族是 更有可能朝着严重传播球菌菌病迈进，而其中许多观察结果 已经结束了这些流行病学的基本机制和遗传发病机理 观察尚未得到充分评估。这些类型的基因组有几个主要障碍 研究宿主遗传背景与环境之间的关系（这里感染）：1） 大多数研究的样本量； 2）处理基因组数据的trabytes的挑战； 3）有限的测序数据 非欧洲人群；和4）确定相关功能读数以确认变体在 相关模型系统。在该U19提案中，项目3汇集了600多个现有的外显子组和基因组 测序数据集并提议收集和顺序超过500个其他情况和对照。这将是 迄今为止，最大的球虫菌病基因研究。该数据分析的关键是该提案的专家 他们的专业知识使我们能够处理数据的数据，并可以使用特定于祖先的方法进行分析。 我们将探讨两个主要的假设：构成祖先特定方法的常见变体 DCM的种族和种族特异性差异或关键免疫信号通路中罕见的遗传变异 增加DCM的风险。这两个假设都不一定是相互排斥的，可以解释一些 已经观察到的疾病关联。除了识别DNA变体外，我们还将执行 ATAC-SEQ，RNA测序研究在功能上验证非编码和剪接变化是由非编码和剪接变化 编码遗传变异。该项目的一个关键方面是它能够与项目1和2迅速集成和 核心C可以验证新型遗传变异及其对免疫途径的影响。它将使我们直接 弥合确定的遗传变异和临床功能之间的差距。