HLA/KIR Region Genetics in Pediatric Arthritis

小儿关节炎中的 HLA/KIR 区域遗传学

• 批准号: 7393220
• 负责人: DAVID N. GLASS
• 金额: $ 40.03万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393220
• 关键词: Adult; Alleles; Area; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Child; Childhood; Chromosomes; Chronic; Chronic Childhood Arthritis; Class; Clinical; Data; Data Analyses; Disease; Disease susceptibility; Doctor of Medicine; Ensure; Ethnic Origin; Family; Gene Combinations; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Glass; Goals; HLA-B Antigens; HLA-DP Antigens; HLA-DR4 Antigen; HLA-DR7 Antigen; HLA-DR8; Haplotypes; Immunoglobulins; Individual; Lead; Ligands; Linkage Disequilibrium; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Maps; Microsatellite Repeats; Minor; Molecular; Natural Killer Cells; Oligonucleotides; Outcome; Parents; Pathogenesis; Pathway interactions; Patients; Polymerase Chain Reaction; Population; Population Control; Predisposition; Protocols documentation; Purpose; Relative (related person); Research Personnel; Resolution; Rheumatoid Arthritis; Risk; Role; Severities; Sex Bias; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Specificity; Stratification; Susceptibility Gene; Systemic disease; Terminology; Testing; Translating; base; clinical phenotype; cohort; comparative; density; disease phenotype; disorder risk; disorder subtype; early onset; functional genomics; gene interaction; high throughput technology; human leukocyte antigen gene; improved; killer inhibitory receptor; programs; response; sample collection

JRA (also known as JIA) includes the commonest chronic autoimmune arthropathies of childhood. The MHC is involved with respect to risk, either susceptibility or protection in a subtype specific manner with strong gender bias' and differences between ethnicities. Multiple MHC effects have been shown, especially in the commonest subtype, so called early onset pauciarticular JRA (Persistent Oligo in the JIA terminology) with three or more MHC regions believed to interact in generating susceptibility. An additional feature of the disease, unlike some other forms of autoimmunity, is the relative absence of common extended or ancestral haplotypes, especially those carrying HLA-DR4 and HLA-DR7 both of which are protective. The three regions include a class I region, or an area telomeric to it, and two class II regions those around HLA DR/DQ and HLA-DP. None of the regions involved are well defined nor were the specific genes involved identified. The alleles marking these regions (HLA-DR8, 11 and HLA-DPB1*0201) are atypical for autoimmunity. This is therefore an unusual MHC contribution to autoimmunity, the elucidation of which lends itself to high throughput technologies. The genetic features, although involving arthritis, are quite distinct from adult rheumatoid arthritis except for about 5% of older children. It is proposed to construct high throughput SNP maps in a family based study. Subtypes have different MHC profiles and in the rarest and most severe form of disease, systemic onset JRA, the MHC effect is rather minimal. In this form, preliminary data involving KIR gene haplotypes is available. Pursuing these KIR gene observations is proposed. The ability to leverage ongoing pheontyping and family based sample collection ensures a large and continuously growing pool of available DMAs for this project. Some of the patients will also have extensive gene expression studies allowing a comprehensive approach to the MHC and KIR genes in JRA and its subtypes.

JRA(也称为JIA)包括儿童时期最常见的慢性自身免疫性关节疾病。MHC以一种具有强烈性别偏见的亚型特定方式涉及风险、易感性或保护，以及种族之间的差异。已经显示了多种MHC效应，特别是在最常见的亚型，即所谓的早发性少关节JRA(JIA术语中的持续性寡聚)，有三个或更多的MHC区域被认为在产生易感性方面相互作用。与其他一些形式的自身免疫不同，这种疾病的另一个特征是相对缺乏共同的传代或祖先 单倍型，尤其是携带人类白细胞抗原-DR4和人类白细胞抗原-DR7的单倍型，这两种单倍型都具有保护性。这三个区域包括一个第I类区域或与其相连的端粒区域，以及两个位于HLADR/DQ和HLADP周围的第II类区域。没有一个涉及的区域被很好地定义，也没有确定涉及的特定基因。标记这些区域的等位基因(人类白细胞抗原-DR8、11和人类白细胞抗原-DPB1*0201)是非典型的自身免疫。因此，这是一种不同寻常的MHC对自身免疫的贡献，它的阐明有助于高通量技术。遗传特征虽然与关节炎有关，但除了大约5%的大一点的儿童外，与成人类风湿性关节炎非常不同。建议在基于家庭的研究中构建高通量的SNP图谱。亚型有不同的MHC谱，在最罕见和最严重的疾病形式-全身性JRA中，MHC的影响相当小。在此表格中，初步 关于KIR基因单倍型的数据是可用的。建议继续进行这些KIR基因的观察。利用正在进行的基因定型和基于家庭的样本收集的能力确保了该项目可用的大量且不断增长的DMA池。一些患者还将进行广泛的基因表达研究，从而全面了解JRA及其亚型的MHC和KIR基因。