Establishing the contributions of monogenic etiologies to hidradenitis suppurativapathogenesis

病理性炎症是临床上各种疾病的主要发病率来源，这些疾病是 以不可逆转的组织损伤为特点。化脓性汗腺炎(HS)是一种常见的炎症性皮肤病 这与其他疾病有共同的特征，包括反复发作的无缘无故的炎症导致 疼痛、增生、异常愈合和纤维化。HS令人衰弱，难以管理，还有许多未满足的问题 医疗需要。值得注意的是，HS迫切需要新的治疗方法，FDA批准的唯一药物未能使 约35%的患者有临床反应。人类基因研究有助于确定药物靶点和优先顺序 提高药物开发成功率。然而，进行的人类遗传学研究相对较少。 对于HS，这些都是在小群体中进行的。此外，尽管非裔美国人有三个 这些研究已将他们排除在HS风险之外。重要的是，没有GWA或Exome广泛的研究 已为HS出版。到目前为止，已经描述了四种HS的单基因病因，其中之一 意味着先天免疫错误(IEI)。IEI是由近500种疾病组成的单基因疾病 广泛研究了导致免疫系统功能不正常的基因，导致病理 炎症、自身免疫和/或增加对感染的易感性。IEI是一系列表型的基础， 将多器官功能障碍扩展到更多的局部结果，其中一些包括HS和/或临床特征重叠 和HS一起。HS和IEI之间在免疫学和临床上有重叠，但IEI并不严格 用HS遗传学研究进行了调查。此外，IEI对盛行病毒的遗传结构做出了贡献 多因素障碍，并可能对携带这些疾病的患者具有重要的临床意义 提供有针对性的干预和个体化筛查的机会。就像我们发现的那样 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 是HS发病机制的重要组成部分。具体地说，我们将首先测试这一假设，即一些患有 HS诊断具有IEI，方法是生成外显子组数据并执行以下诊断分析 确认已识别的突变。接下来，我们将检验IEI通路是HS的组成部分的假设 发病机制。我们将使用外显子组数据的负荷测试和全基因组关联研究来识别 与HS相关的基因、途径和细胞类型，然后确定IEI基因和 HS中的路径。我们的方法是利用我们与之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经营HS临床试验的行业合作伙伴。这个 这些研究的成功完成将有助于确定患有IEI的HS研究参与者的子集(一些 这将具有直接的临床相关性)，将确定HS中IEI的患病率，并将识别IEI 与没有IEI的HS患者相关的通路。总而言之，这些结果将为药物提供理论基础。 在HS中改变用途，也可能有助于改进控制致病性炎症的策略。

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.