Systems-level genetic patterns underlying disseminated coccidioidomycosis in humans

人类播散性球孢子菌病的系统级遗传模式

• 批准号: 10337578
• 负责人: Yves A. Lussier
• 金额: $ 20.42万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337578
• 关键词: Acute; Address; African American; Alleles; Automobile Driving; Biochemical; Biological; Biological Process; Biology; Brain; Candidate Disease Gene; Caring; Case Study; Categories; Chronic; Clinical; Coccidioides; Coccidioidomycosis; Code; Communicable Diseases; Complex; DNA; Data; Databases; Disease; Disease susceptibility; Emerging Communicable Diseases; Equilibrium; Exogenous Factors; Filipino; Foundations; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Genotype; Guidelines; HLA Antigens; Haplotypes; Heterogeneity; Human; Human Genetics; IFNGR1 gene; IL12RB1 gene; Immune; Immune response; Immune system; Immunocompetent; Immunogenetics; Immunological Models; Immunosuppression; Infection; Inhalation; Knowledge; Life; Lung; Medical; Modeling; Molecular; Mutation; Mycoses; National Institute of Allergy and Infectious Disease; Organ; Participant; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patients; Pattern; Phenotype; Play; Pneumonia; Positioning Attribute; Predisposition; Proteins; Quantitative Trait Loci; Recommendation; Resistance; Resources; Risk; Role; STAT1 gene; STAT3 gene; Sample Size; Sampling Studies; Signal Transduction; Soil; Stimulus; Symptoms; System; Systems Analysis; Testing; Therapeutic; Time; Variant; adverse outcome; bone; causal variant; clinical care; cohort; desert fever; design; exome; exome sequencing; experience; flu; fungus; genetic architecture; genetic risk factor; genome-wide; genome-wide analysis; genotyped patients; high risk; human leukocyte antigen testing; insight; novel; pathogen; pathogen exposure; pathogenic fungus; rare variant; recruit; response; risk variant; skin damage; whole genome

PROJECT SUMMARY Disseminated coccidioidomycosis (DCM) is a rare and potentially life-threatening consequence of infection with a desert soil dwelling fungal pathogen native to the Southwestern USA (Coccidioides spp.). The reason why a subset (<5%) of otherwise healthy people develop this adverse outcome after infection while most others do not is largely unknown. However, evidence points to genetics, primarily involving variation in the immune system. To discover the systems genetic patterns and pathways associated with DCM, we will examine the differential distribution of variants in biologically meaningful gene sets at genome-wide scale to find patterns that underlie disease susceptibility. Focusing on aggregated systems-level sets allows us to find patterns in the presence of cross-patient differences, and substantially increases our statistical discovery power by reducing the number of features being directly tested. This study will be the first of its scope and kind, using the largest cohort ever assembled for this disease (DNA collected from 147 susceptible DCM cases and 388 resistant controls presenting as self-limited pulmonary coccidioidomycosis). The data and results gathered under this proposal thus present a unique resource to lay important foundations for the study of DCM pathogenesis. The DNA has been both (i) genome-wide genotyped for common variation, and (ii) exome sequenced to look for rare, protein-altering variation. In our first Aim, we will study the genotype data in three different ways. First, we will look for association between DCM and variation in the human leukocyte antigen region (HLA) which plays an important role in many infectious diseases. Second, we will look at the distribution of patient genotypes at infection-relevant reQTL variant sets to model if DCM versus PUL have differences correlated with their phenotype. These reQTL variant sets are groups of DNA positions where different alleles can cause stronger or weaker gene expression responses after infection or stimulation, and differences between DCM and PUL at those positions could imply that their Coccidioides-response capacity may differ. Third, we will conduct a pathway-association study using both hypothesis-driven and unbiasedly selected pathways (sets of genes) to see if these genesets are enriched for variants associated with DCM. For our second Aim, we will analyze the rare variants found in patient exomes to compare whether DCM participants have an excess of rare and protein-damaging mutations in immune or other candidate pathways. We will use a two-step version of the small sample size optimized Sequence Kernel Association test, comparing the distribution of these mutations between DCM and PUL participants. Using a pathway, or gene set approach allows us to look at differentially impacted systems, rather than requiring each participant to carry the same single-gene mutation. Results of the studies under these two aims will lead to a better understanding the human genetic variation associated with DCM, will help us understand this emerging infectious disease (NIAID Category C), identify people at lower or higher risk, and ultimately build towards improvements in clinical care and patient experience.

项目概要 播散性球孢子菌病 (DCM) 是一种罕见且可能危及生命的感染后果 与原产于美国西南部的沙漠土壤真菌病原体（球孢子菌属）一起。原因 为什么一小部分（<5%）原本健康的人在感染后会出现这种不良后果，而大多数其他人则出现这种不良后果 很大程度上不知道。然而，有证据表明遗传学，主要涉及免疫变异 系统。为了发现与 DCM 相关的系统遗传模式和途径，我们将检查 在全基因组范围内对具有生物学意义的基因组中的变异进行差异分布以寻找模式 是疾病易感性的基础。专注于聚合的系统级集合使我们能够在 跨患者差异的存在，并通过减少显着提高我们的统计发现能力 直接测试的功能数量。这项研究将是其范围和类型中的第一个，使用最大的 曾针对该疾病组建的队列（从 147 例易感 DCM 病例和 388 例耐药病例中收集 DNA） 对照表现为自限性肺球孢子菌病）。在此收集的数据和结果 因此，该提案提供了独特的资源，为 DCM 发病机制的研究奠定重要基础。这 DNA 已 (i) 对常见变异进行全基因组基因分型，以及 (ii) 对外显子组进行测序以寻找 罕见的蛋白质改变变异。在我们的第一个目标中，我们将以三种不同的方式研究基因型数据。第一的， 我们将寻找 DCM 与人类白细胞抗原区 (HLA) 变异之间的关联， 在许多传染病中发挥着重要作用。其次，我们来看一下患者的分布情况。 感染相关 reQTL 变异集的基因型用于建模 DCM 与 PUL 是否存在差异相关 与他们的表型。这些 reQTL 变异集是不同等位基因可能导致的 DNA 位置组 感染或刺激后基因表达反应更强或更弱，以及 DCM 和 DCM 之间的差异 这些位置的 PUL 可能意味着它们的球孢子菌响应能力可能不同。三、我们将进行 使用假设驱动和公正选择的途径（基因组）进行途径关联研究 看看这些基因组是否富含与 DCM 相关的变异。对于我们的第二个目标，我们将分析 在患者外显子组中发现罕见变异，以比较 DCM 参与者是否具有过量的罕见变异和 免疫或其他候选途径中的蛋白质破坏性突变。我们将使用一个两步版本 小样本量优化的序列核关联测试，比较这些突变的分布 DCM 和 PUL 参与者之间。使用途径或基因组方法使我们能够以不同的方式看待 受影响的系统，而不是要求每个参与者携带相同的单基因突变。结果 这两个目标下的研究将有助于更好地了解与以下疾病相关的人类遗传变异： DCM，将帮助我们了解这种新出现的传染病（NIAID C 类），识别处于较低或较低水平的人 更高的风险，并最终改善临床护理和患者体验。