Identification of genetic loci and pathways underlying hidradenitis suppurativa risk

摘要 化脓性汗腺炎（HS）是一种慢性炎症性皮肤病，主要影响大汗腺， 身体的各个部位，并表现为疼痛的结节、脓肿、窦道和疤痕。HS是一 遗传和环境因素起关键作用的多因素疾病。遗传学一直是 与HS风险有关，30%-40%的患者报告有HS家族史，但HS的遗传结构 HS定义不明确。此外，全基因组关联研究（GWAS），一种建立的方法， 阐明复杂疾病的遗传病因，从未在HS患者中进行过。这个项目 将利用来自两个机构来源的现有临床和基因型数据的成熟队列， 鉴定和验证HS易感基因座。其中包括大型、特色鲜明、以社区为基础的 北方Kaiser Permanente成人健康与老龄化（GERA）队列的遗传流行病学研究 加州（n= 102，854），以及全面的、基于三级医疗的Partners Healthcare Biobank队列 （n= 104 008）。使用GWAS方法，我们将在两个独立的基因组中识别和验证HS易感基因座。 通过评估吸烟对遗传风险的影响， 和身体质量指数然后，我们将结合GERA、Partners Biobank和UK进行荟萃分析。 生物样本库队列数据（n~ 500，000），并使用 23和我的队列。最后，我们将通过执行以下操作来检查我们确定的SNP的功能作用： 全面的功能注释和途径分析，以确定参与 HS发病机制。本提案的总体科学目标是确定和验证HS 易感基因座，检查基因-环境相互作用，并深入了解分子 参与其发病机制的途径，其长期目标是发现推定的新治疗方法， 目标的通过关注HS的遗传病因学，该提案对NIAMS的资助做出了高度响应 公告机会PA-18-718专门解决遗传易感性研究作为一个定义的领域 感兴趣的，并题为：加速在Hidradenitis Suppurativa的基础和转化研究。我们 方法是创新的，因为它提出了一个GWAS，这是以前没有执行过的。 未充分研究的疾病，并建议研究基因与环境的相互作用。我们的发现不仅会让我们 关于HS易感性遗传学的有价值的信息，但也将作为一个公开的资源 为科学界。这项研究具有重要意义，因为它将提供一个全面的 HS遗传风险的图片，并将为新的诊断和治疗机会铺平道路。这么高- 一项影响提案旨在确定遗传性HS易感性增加的潜在机制，以改善我们的 了解HS发病机制，并为开发新的治疗方案提供信息，以更好地控制和 最终预防这种使人衰弱的慢性皮肤病的发作。

ABSTRACT Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body and presenting with painful nodules, abscesses, sinus tracts, and scarring. HS is a multifactorial disease in which genetic and environmental factors play a key role. Genetic has been strongly implicated in HS risk, with 30%–40% of patients reporting a family history of HS, but the genetic architecture of HS is poorly defined. Furthermore, genome wide association studies (GWAS), an established approach for elucidating genetic etiology of complex disease, have never been conducted in patients with HS. This project will utilize well-established cohorts of existing clinical and genotyped data from two institutional sources to identify and validate HS susceptibility loci. These include the large, well-characterized, community-based Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort in Kaiser Permanente Northern California (n=102,854), and the comprehensive, tertiary-care based Partners Healthcare Biobank cohort (n=104,008). Using a GWAS approach, we will identify and validate HS susceptibility loci in two independent cohorts and examine gene-environment interactions by assessing modifications in genetic risk with smoking and body mass index. We will then perform a meta-analysis combining GERA, Partners Biobank and UK Biobank cohort data (n~500,000) and validate all identified HS loci using summary statistics provided by the 23andMe cohort. Finally, we will examine the functional role of our identified SNPs by performing comprehensive functional annotation and pathway analysis to identify molecular signaling pathways involved in HS pathogenesis. The overall scientific objective of this proposal is to identify and validate HS susceptibility loci, examine gene-environment interactions, and gain insight into the molecular pathway involved in its pathogenesis with the long-term goal of uncovering putative new therapeutic targets. By focusing on the genetic etiology of HS, this proposal is highly responsive to the NIAMS Funding Announcement Opportunity PA-18-718 specifically addressing genetic susceptibility studies as a defined area of interest, and entitled: Accelerating Basic and Translational Research in Hidradenitis Suppurativa. Our approach is innovative because it proposes a GWAS, which has not previously been performed for this understudied disorder and proposes to study gene-environmental interactions. Our findings will not only yield valuable information on the genetics of HS susceptibility, but also will serve as a publicly accessible resource for the scientific community. The proposed research is significant because it will provide a comprehensive picture of HS genetic risk and will pave the way for new diagnostic and therapeutic opportunities. This high- impact proposal seeks to identify mechanisms underlying increased inherited HS susceptibility to improve our understanding of HS pathogenesis and inform development of novel therapeutic options to better control and ultimately prevent the onset of this debilitating, chronic skin disease.