Evaluation of the Genetics of Hidradenitis Suppurativa

项目总结/摘要 化脓性汗腺炎（HS）是一种慢性、疼痛、严重的炎症性皮肤病， 影响患者生活质量。HS发生在高达0.5%的一般人群中，并且发病率 在过去的十年里继续增加。先前表征HS患者队列的研究 35-38%的患者报告有家族史，57%的患者报告有一级或二级受累 亲戚虽然HS影响所有血统的个人，但它似乎会影响女性和非洲人， 美国人（AA）。发病年龄通常在青春期/青年期（15-25岁）， 症状在一生中的大部分时间里都会持续。迄今为止，已经描述了可能导致HS的遗传变异 在27个家庭和15个散发病例中，但在后续筛查研究中， 21个家系中仅5个检出，68例散发病例中仅2例检出。基因变异与 自身炎症，异常卵泡分化，和HS已报告在四个基因，包括三个 编码γ-分泌酶复合物亚基的基因。然而，HS的家族复发风险和 大多数患者对HS的遗传贡献知之甚少。我们假设系统性的 对HS的遗传贡献的检查将导致基因和致病性的鉴定， 炎症通路参与疾病的发作和进展。 在这项研究中，我们建议在一个新的700例HS患者队列中检查HS的遗传基础。参与者 正在从全国最大的HS人口之一招募北美HS主席 具有HS临床试验经验的指南委员会。在重新提交时，我们有 已经收集了561例HS患者的临床数据、家族史和DNA样本，其中约50%为非洲裔美国人 80%的女性。我们的目标是在R21资助期间招募至少700名患者。我们将描述 疾病严重程度的分布和计算的同胞相对风险，作为家庭聚集的量度，以及 确定基于年龄、性别和种族的风险差异。为了进行无偏见的搜索， 与HS相关的变异，我们将进行全基因组关联研究（GWAS）。对于这个分析，我们 将利用已建立的病例对照匹配方法和广泛的全基因组序列， 数据可从Trans-Omics for Precision Medicine（TOPMed）项目和基因组测序中获得 项目（GSP），以适当地选择控件。识别显示以下证据的遗传变异： 与HS疾病状态的关联将提供用于进一步验证的靶变体和候选基因， 生物学研究，以发现新的治疗方法，并可能预防疾病。

PROJECT SUMMARY/ABSTRACT Hidradenitis suppurativa (HS) is a chronic, painful, severe, inflammatory skin disease that has a devastating effect on patient quality of life. HS occurs in up to 0.5% of the general population, and the incidence has continued to increase over the last decade. Previous studies characterizing cohorts of HS patients have reported family history in 35-38% of patients, and 57% of our patients report an affected first or second degree relative. While HS affects individuals of all ancestries, it appears to disproportionally affect women and African- Americans (AA). The age of onset that is typically in adolescence/young adulthood (ages 15-25 years old) and symptoms continue throughout much of life. To date, genetic variants that may cause HS have been described in 27 families and 15 sporadic cases, but in follow-up screening studies, pathogenic genetic variants were detected in only 5 of 21 families and 2 of 68 patients with sporadic cases of HS. Genetic variants implicated in autoinflammation, abnormal follicular differentiation, and HS have been reported in four genes, including three genes encoding subunits of the gamma-secretase complex. However, the familial recurrence risk of HS and genetic contributions to HS are poorly understood for most patients. We hypothesize that systematic examination of the genetic contributions to HS will lead to the identification of genes and pathogenic, inflammatory pathways involved in disease onset and progression. In this study, we propose to examine the genetic basis of HS in a new cohort of 700 HS patients. Participants are being recruited from one of the largest HS populations in the country by chair of the North American HS Guidelines Committee who has experience with clinical trials for HS. At the time of re-submission, we have already collected clinical data, family history, and DNA specimens for 561 HS patients, ~50% African American and ~80% female. We aim to recruit at least 700 patients during the R21 funding period. We will characterize the distribution of disease severity and calculate sibling relative risk, as a measure of familial aggregation, and identify differences in risk based on age, sex, and ethnicity. To perform an unbiased search for new genetic variants associated with HS, we will perform a genome-wide association study (GWAS). For this analysis, we will make use of established methods for case-control matching and the extensive genome-wide sequence data available from the Trans-Omics for Precision Medicine (TOPMed) project and Genome Sequencing Project (GSP) to appropriately select controls. Identification of genetic variants that show evidence for association with HS disease status will provide target variants and candidate genes for further validation and biological study to detect new treatments and possibly prevention of disease.