Establishing the contributions of monogenic etiologies to hidradenitis suppurativapathogenesis

确定单基因病因对化脓性汗腺炎发病机制的贡献

基本信息

批准号：
10595266
负责人：
Lynn Petukhova
金额：
$ 72.1万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595266
关键词：
African American population Architecture Atopic Dermatitis Autoimmunity Biological Caring Clinical Clinical Data Clinical Trials Cohort Studies Cytokine Signaling Data Diagnosis Diagnostic Disease Drug Targeting Electronics Etiology Exclusion FDA approved Fibrosis Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic study Genotype Hereditary Disease Hidradenitis Hidradenitis Suppurativa Human Genetics Hyperplasia Immune Immunity Immunologics Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Intervention Level of Evidence Mediating Medical Mendelian disorder Meta-Analysis Morbidity - disease rate Mutation Organ Outcome Pain Participant Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Population Predisposition Prevalence Public Domains Publishing Research Risk Role Running STAT1 gene Sampling Series Signal Pathway Source Testing Time Tissues Validation biobank body system cell type clinical sequencing clinically relevant cohort comorbidity drug development drug repurposing exome exome sequencing genetic architecture genome wide association study genome-wide healing immune system function improved in silico industry partner older patient response screening skin disorder skin lesion success therapeutic target

项目摘要

Pathological inflammation is a source of substantial morbidity underlying clinically diverse diseases that are marked by irreversible tissue damage. Hidradenitis suppurativa (HS) is a prevalent inflammatory skin disease that shares features with these other disorders, including repeated bouts of unprovoked inflammation causing pain, hyperplasia, aberrant healing, and fibrosis. HS is debilitating, difficult to manage, and has many unmet medical needs. Notably, HS is in dire need of new treatments, with the lone FDA-approved drug failing to illicit a clinical response in ~35% of patients. Human genetic studies help to identify and prioritize drug targets and improve drug development success rates. However, relatively few human genetic studies have been performed for HS and these have been conducted in small cohorts. Furthermore, although African Americans are at three times the risk of HS, they have been excluded from those studies. Importantly, no GWAS or exome wide studies have been published for HS. To date, four monogenic etiologies have been described for HS, one of which implicates an inborn error of immunity (IEI). IEI are single-gene disorders comprising a class of nearly 500 extensively studied genes that cause improper function of the immune system, resulting in pathological inflammation, autoimmunity, and/or increased susceptibility to infection. IEI underlie a range of phenotypes that span multi-organ dysfunction to more focal outcomes, and some include HS and/or clinical features that overlap with HS. There is immunological and clinical overlap between HS and IEI, and yet IEI have not been rigorously investigated with HS genetic studies. Furthermore, IEI contribute to the genetic architecture of prevalent multifactorial disorders and can have important clinical implications for the patients that harbor them by presenting opportunities for targeted interventions and individualized screening. As was found to be the case for other inflammatory diseases such as inflammatory bowel disease and atopic dermatitis, we hypothesize IEI are important components of HS pathogenesis. Specifically, we will first test the hypothesis that some people with an HS diagnosis have an IEI by generating exome data and performing a diagnostic analysis followed by validation of identified mutations. Next, we will test the hypothesis that IEI pathways are a component of HS pathogenesis. We will use burden testing with exome data and genome-wide association studies to identify genes, pathways, and cell types that are relevant to HS and then determine the prevalence of IEI genes and pathways in HS. Our approach is to leverage large HS cohorts with ancestral diversity that we have built with clinical collaborators who specialize in HS treatment and industry partners running HS clinical trials. The successful completion of these studies will help to identify subsets of HS research participants with IEI (some of which will have immediate clinical relevance), will determine the prevalence of IEI in HS, and will identify IEI pathways that are relevant to HS patients without an IEI. Together these results will provide the rationale for drug repurposing in HS and may also help to improve strategies for managing pathogenic inflammation.

病理性炎症是临床多种疾病的重大发病根源，这些疾病以不可逆的组织损伤为标志。化脓性汗腺炎 (HS) 是一种常见的炎症性皮肤病与这些其他疾病有共同的特征，包括反复发作的无端炎症导致疼痛、增生、异常愈合和纤维化。 HS 令人衰弱，难以管理，并且有许多未满足的问题医疗需求。值得注意的是，HS 迫切需要新的治疗方法，而 FDA 批准的唯一药物未能非法约 35% 的患者有临床反应。人类遗传学研究有助于确定药物靶点并确定其优先顺序提高药物开发的成功率。然而，人类遗传学研究相对较少对于 HS，这些都是在小队列中进行的。此外，尽管非裔美国人三岁倍的 HS 风险，因此他们被排除在这些研究之外。重要的是，没有 GWAS 或外显子组广泛研究已为 HS 发布。迄今为止，已描述了 HS 的四种单基因病因，其中之一涉及先天性免疫错误（IEI）。 IEI 是单基因疾病，包含近 500 种类型广泛研究的基因会导致免疫系统功能异常，从而导致病理性的炎症、自身免疫和/或感染易感性增加。 IEI 是一系列表型的基础跨越多器官功能障碍到更多的焦点结果，有些包括重叠的 HS 和/或临床特征与HS。 HS 和 IEI 之间存在免疫学和临床重叠，但 IEI 尚未经过严格的研究 HS 遗传学研究进行了调查。此外，IEI 对流行病的遗传结构做出了贡献多因素疾病，并且可能对患有这些疾病的患者产生重要的临床意义提供有针对性的干预和个性化筛查的机会。正如我们发现的情况一样其他炎症性疾病，如炎症性肠病和特应性皮炎，我们假设 IEI 是 HS 发病机制的重要组成部分。具体来说，我们将首先检验以下假设：有些人患有 HS 诊断通过生成外显子组数据并执行诊断分析来进行 IEI，然后验证已识别的突变。接下来，我们将检验 IEI 途径是 HS 组成部分的假设发病。我们将使用外显子组数据和全基因组关联研究的负担测试来识别与 HS 相关的基因、途径和细胞类型，然后确定 IEI 基因和的患病率 HS 中的途径。我们的方法是利用我们建立的具有祖先多样性的大型 HS 队列专门从事热射病治疗的临床合作者和运行热射病临床试验的行业合作伙伴。这成功完成这些研究将有助于识别 IEI 的 HS 研究参与者子集（其中一些这将具有直接的临床意义），将确定 HS 中 IEI 的患病率，并将识别 IEI 与没有 IEI 的 HS 患者相关的途径。这些结果将为药物提供理论依据在 HS 中重新利用，也可能有助于改进控制致病性炎症的策略。