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

• 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
• 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

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.

病理性炎症是导致临床上多种疾病的实质性发病率的来源， 以不可逆的组织损伤为特征。化脓性汗症（HS）是一种流行的炎症性皮肤病 与这些其他疾病有共同的特征，包括反复发作的无端炎症， 疼痛、增生、异常愈合和纤维化。HS是衰弱的，难以管理，有许多未满足的 医疗需求。值得注意的是，HS迫切需要新的治疗方法，唯一一种FDA批准的药物未能非法使用， 约35%的患者有临床反应。人类遗传学研究有助于确定和优先考虑药物靶点， 提高药物开发成功率。然而，人类基因研究相对较少 对于HS，这些已经在小队列中进行。此外，虽然非洲裔美国人在三个 倍的风险HS，他们已被排除在这些研究。重要的是，没有GWAS或外显子组范围的研究 已为HS出版。迄今为止，已经描述了HS的四种单基因病因，其中之一是 先天性免疫缺陷（Inborn Error of Immunity，IEI）IEI是单基因疾病，包括近500种 广泛研究了导致免疫系统功能异常、导致病理性疾病的基因 炎症、自身免疫和/或对感染的易感性增加。IEI是一系列表型的基础， 跨越多器官功能障碍到更集中的结果，有些包括重叠的HS和/或临床特征 在HS。HS和IEI之间存在免疫学和临床重叠，但IEI尚未被严格评估。 通过HS遗传学研究进行调查。此外，IEI有助于流行的遗传结构， 多因素疾病，并可能有重要的临床意义的病人，他们窝藏他们， 提供有针对性的干预和个性化筛查的机会。正如人们发现的那样， 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。具体地说，我们将首先检验一个假设，即有些人 HS诊断通过产生外显子组数据并进行诊断分析， 验证已鉴定的突变。接下来，我们将检验IEI通路是HS的一个组成部分的假设。 发病机制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确定 与HS相关的基因、途径和细胞类型，然后决定IEI基因的患病率， 在HS的路径。我们的方法是利用我们已经建立的具有祖先多样性的大型HS队列， 专门从事HS治疗的临床合作者和运行HS临床试验的行业合作伙伴。的 这些研究的成功完成将有助于识别患有IEI的HS研究参与者的子集（其中一些 具有直接的临床相关性），将决定HS中IEI的患病率，并将识别IEI 与没有IEI的HS患者相关的通路。这些结果将为药物治疗提供依据。 在HS中重新利用，也可能有助于改善管理致病性炎症的策略。