Integrative Analysis of Genomic Risk Factors in Juvenile Idiopathic Arthritis

描述（由申请人提供）：幼年特发性关节炎（JIA），约1/10，000的北美儿童，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、组织损伤和身体不动之外，慢性疾病活动还导致永久性身材矮小和肢体畸形。与许多其他复杂的多基因自身免疫性疾病类似，JIA有明显的遗传成分，但所有已知的遗传风险因素解释的疾病遗传性不到20%。其中大部分归因于主要组织相容性的变化 (MHC)基因座，但明确的高分辨率鉴定MHC协会在JIA还没有定论。JIA目前被分为七个临床亚型，基于一个几乎没有研究或临床实用性的分类模式，因为10-50%的病例被归类为“未分化”。基于血清自身抗体和免疫缺陷的其他分子生物标志物的存在的生物学和分子证据表明，现有的7个JIA亚型可以分为两大类-亚型，主要代表血清阳性自身免疫（AID）疾病或血清阴性自身炎症（AIF）疾病。AID与AIF样JIA亚型的遗传风险因素是否不同尚不清楚，特别是因为传统的遗传关联研究方法在存在显著表型异质性的情况下难以鉴定具有亚型特异性效应的基因座。为了验证不同的遗传危险因素是临床观察到的AID与AIF样JIA亚型差异的基础这一假设，并确定共享和亚型不同的遗传易感性位点，我建议使用亚型敏感的GWAS来确定JIA疾病亚型特异性遗传学关联，评估JIA亚型之间不同或共享的功能性HLA关联的证据，并测试所鉴定的遗传关联是否可用于预测疾病易感性，区分属于AID与AIF样JIA类别的患者，以及将目前定义为患有未分化疾病的患者重新分类。这里提出的分析方法集成了基因组筛选，疾病建模和预测，并使用表达和功能数据资源，以更好地了解JIA的病因。这项工作的成功完成将可能产生新的生物分子或基于通路的目标，用于开发JIA儿童和其他相关风湿性或免疫性疾病患者的治疗药物。

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.