Identification of genetic loci and pathways underlying hidradenitis suppurativa risk

识别化脓性汗腺炎风险的遗传位点和途径

基本信息

批准号：
10256622
负责人：
MARYAM Mandana ASGARI
金额：
$ 15.52万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10256622
关键词：
Abscess Address Adult Advocate Affect Aging Apocrine Glands Area Arthritis Axilla Basic Science Blood specimen Body mass index Breast Buttocks California Caregivers Chronic Cicatrix Clinical Communities Complex Consent Cyst Data Development Disease Electronic Health Record Ensure Environmental Risk Factor Etiology Evaluation Family history of Foundations Functional disorder Funding Funding Opportunities Future Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Skin Diseases Genomic Segment Genomics Genotype Geography Goals Health Healthcare Hidradenitis Suppurativa Individual Inflammatory Inguinal region Inherited Institutes Institution Investigation Knowledge Lead Letters Medical Genetics Meta-Analysis Modification Molecular Musculoskeletal Mutation National Institute of Arthritis and Musculoskeletal and Skin Diseases Nodule Pain Pathogenesis Pathology Pathway Analysis Pathway interactions Patients Play Population Genetics Predisposition Principal Investigator Proteins Reporting Research Resources Risk Role Sampling Signal Pathway Single Nucleotide Polymorphism Sinus Smoking Smoking Status Source Susceptibility Gene Testing Therapeutic Tissues Translational Research Uncertainty Variant base biobank causal variant cell type chronic inflammatory skin cohort cost efficient design disorder risk epidemiology study epigenomics gamma secretase gene environment interaction genetic architecture genetic association genetic epidemiology genetic resource genetic variant genome wide association study genomic locus hair follicle disorder improved in silico innovation insight interest new therapeutic target novel novel diagnostics novel therapeutics population stratification presenilin-1 prevent repository sex skin disorder statistics tertiary care

Abscess Address Adult Advocate Affect Aging Apocrine Glands Area Arthritis Axilla Basic Science Blood specimen Body mass index Breast Buttocks California Caregivers Chronic Cicatrix Clinical Communities Complex Consent Cyst Data Development Disease Electronic Health Record Ensure Environmental Risk Factor Etiology Evaluation Family history of Foundations Functional disorder Funding Funding Opportunities Future Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Skin Diseases Genomic Segment Genomics Genotype Geography Goals Health Healthcare Hidradenitis Suppurativa Individual Inflammatory Inguinal region Inherited Institutes Institution Investigation Knowledge Lead Letters Medical Genetics Meta-Analysis Modification Molecular Musculoskeletal Mutation National Institute of Arthritis and Musculoskeletal and Skin Diseases Nodule Pain Pathogenesis Pathology Pathway Analysis Pathway interactions Patients Play Population Genetics Predisposition Principal Investigator Proteins Reporting Research Resources Risk Role Sampling Signal Pathway Single Nucleotide Polymorphism Sinus Smoking Smoking Status Source Susceptibility Gene Testing Therapeutic Tissues Translational Research Uncertainty Variant base biobank causal variant cell type chronic inflammatory skin cohort cost efficient design disorder risk epidemiology study epigenomics gamma secretase gene environment interaction genetic architecture genetic association genetic epidemiology genetic resource genetic variant genome wide association study genomic locus hair follicle disorder improved in silico innovation insight interest new therapeutic target novel novel diagnostics novel therapeutics population stratification presenilin-1 prevent repository sex skin disorder statistics tertiary care

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项目摘要

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.

抽象的 Hidradenenitis purativa（HS）是一种慢性炎症性皮肤疾病，主要影响富含垂体的腺体身体的区域，并出现疼痛的结节，脓肿，窦道和疤痕。 HS是一个多因素疾病，其中遗传和环境因素起着关键作用。遗传一直很强烈在HS风险中实施，有30％–40％报告HS家族史的患者，但 HS的定义很差。此外，基因组广泛的关联研究（GWAS），一种已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。这个项目将利用从两个机构来源到现有的临床和基因分型数据的良好人群识别和验证HS敏感性局部。其中包括大型，良好的，基于社区的 Kaiser Permanente Northern的成人健康与衰老（GERA）队列的遗传流行病学研究加利福尼亚州（n = 102,854），以及综合的，三级护理的合作伙伴医疗生物银行队列（n = 104,008）。使用GWAS方法，我们将在两个独立通过评估吸烟的遗传风险修饰，研究并检查基因环境相互作用和体重指数。然后，我们将进行一项结合GERA，Partners Biobank和UK的荟萃分析生物银行队列数据（N〜500,000），并使用摘要统计数据验证了所有识别HS基因座 23AndMe队列。最后，我们将通过执行我们已识别的SNP的功能作用全面的功能注释和途径分析，以识别涉及的分子信号通路 HS发病机理。该提案的总体科学目标是识别和验证HS 敏感性局部，检查基因环境的相互作用，并深入了解分子涉及其发病机理的途径，其长期目标是发现推定的新疗法目标。通过关注HS的遗传病因，该建议对NIAMS的资金有很高的反应公告机会PA-18-718专门针对遗传易感性研究作为定义的区域感兴趣的和标题：加速化合物Hidradenitis的基本和转化研究。我们的方法是创新的，因为它提出了GWAS，以前尚未为此执行研究基因 - 环境相互作用的研究和建议。我们的发现不仅会产生关于HS敏感性的遗传学的有价值的信息，但也将作为公共访问的资源对于科学界。拟议的研究很重要，因为它将提供全面的 HS遗传风险的图片，将为新的诊断和治疗机会铺平道路。这个高影响提案旨在确定遗传性的HS易感性提高以改善我们的机制了解HS发病机理，并为新型治疗选择的发展提供信息，以更好地控制和最终阻止这种衰弱的慢性皮肤疾病的发作。