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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：
9976890
负责人：
MARYAM Mandana ASGARI
金额：
$ 20.34万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976890
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

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.

摘要