Integrative Analysis of Genomic Risk Factors in Juvenile Idiopathic Arthritis

幼年特发性关节炎基因组危险因素的综合分析

• 批准号: 8717915
• 负责人: Yun Rose Li
• 金额: $ 4.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717915
• 关键词: Accounting; Affect; Algorithms; Alleles; American; Amino Acids; Antigenic Variation; Antigens; Arthritis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological; Biological Markers; Case-Control Studies; Cell Surface Receptors; Characteristics; Child; Childhood; Chronic; Chronic Childhood Arthritis; Chronic Disease; Classification; Clinical; Complement; Complex; Computer Simulation; Crohn' s disease; Data; Data Set; Defect; Development; Diagnosis; Disease; Disease model; Disease susceptibility; Early Diagnosis; Early treatment; Epitopes; Etiology; Exclusion; Genetic; Genetic Epistasis; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genomics; Genotype; HLA Antigens; Health; Hereditary Disease; Heritability; Heterogeneity; Histocompatibility; Immune; Immune System Diseases; Inflammatory; Intervention; Lead; Left; Life; Limb structure; Link; Machine Learning; Maps; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mutation; Pain; Pathway interactions; Patients; Polyarthritides; Population; Predisposition; Psoriasis; Recurrence; Research; Research Design; Resolution; Resources; Rheumatoid Arthritis; Risk; Risk Factors; Role; Serological; Serum; Siblings; Single Nucleotide Polymorphism; Specificity; TNFRSF10A gene; Testing; Therapeutic Agents; Tissues; Training; Undifferentiated; United States; Validation; Variant; Work; arthropathies; base; case control; cohort; disability; disease classification; disorder risk; disorder subtype; evidence base; genetic analysis; genetic association; genetic risk factor; genome wide association study; genome-wide analysis; novel; risk variant; screening; tool

DESCRIPTION (provided by applicant): Juvenile Idiopathic Arthritis (JIA), afflicting ~1 in 10,000 North American Children, encompasses a highly heterogeneous group of chronic, immune-mediated joint disorders. Aside from causing severe pain, tissue damage, and physical immobility, chronic disease activity leads to permanent short stature and limb disfigurement. Similar to a number of other complex polygenic autoimmune diseases, there is a clear heritable component to JIA, but all known genetic risk factors explain less than 20% of disease heritability. The majority of this is attributable to variation across the Major Histocompatibility (MHC) locus, yet definitive high-resolution identification of MHC associations in JIA have not been conclusive. JIA is currently classified into seven clinical subtypes, based on a classification schema that has little research or clinical utility, since 10-50% of cases are classified as "undifferentiated". Biological and molecular evidence based on the presence of serum autoantibodies and other molecular biomarkers of immunological defects suggest that the existing seven JIA subtypes could be grouped into two major classes-subtypes that represent either predominantly seropositive autoimmune (AID) diseases or seronegative autoinflammatory (AIF) diseases. Whether genetic risk factors differ for AID versus AIF-like JIA subtypes is unknown, especially since the traditional approach to genetic association studies is poorly powered to identify loci with subtype- specific effects in the presence of significant phenotypic heterogeneity. To test the hypothesis that distinct genetic risk factors underlie the clinically observed differences in AID versus AIF-like JIA subtypes and identify both shared and subtype-distinct genetic susceptibility loci, I propose to use a subtype-sensitive GWAS to identify JIA disease subtype-specific genetics associations, evaluate evidence for functional HLA associations that are distinct or shared across JIA subtypes, and test if the identified genetic associations can be used to predict disease susceptibility, distinguish patients who belong to AID versus AIF-like JIA classes, and reclassify patients currently defined as having undifferentiated disease. The analysis approach proposed here integrates genomic screening, disease modeling and prediction, and the use of expression and functional data resources to better understand the etiology of JIA. The successful completion of this work will likely yield novel biomolecular or pathway-based targets for the development of therapeutic agents for children with JIA and patients with other related rheumatological or immunological diseases.

描述（由申请人提供）：青少年特发性关节炎（JIA），在10,000名北美儿童中约有1人患病，包括一组高度异质性的慢性免疫介导的关节疾病。除了引起剧烈疼痛、组织损伤和身体不能动外，慢性疾病活动还会导致永久性身材矮小和肢体毁容。与许多其他复杂的多基因自身免疫性疾病类似，JIA有明确的遗传成分，但所有已知的遗传风险因素只能解释不到20%的疾病遗传性。这主要归因于主要组织相容性的差异