HLA/KIR Region Genetics in Pediatric Arthritis

小儿关节炎中的 HLA/KIR 区域遗传学

• 批准号: 7599532
• 负责人: DAVID N. GLASS
• 金额: $ 39.67万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599532
• 关键词: Adult; Alleles; Area; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Child; Childhood; Chromosomes; Chronic; Chronic Childhood Arthritis; Clinical; Data; Data Analyses; Disease; Disease susceptibility; Doctor of Medicine; Ensure; Ethnic Origin; Family; Gene Combinations; Gene Expression; Genes; Genetic; 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; 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; arthropathies; base; clinical phenotype; clinical practice; cohort; comparative; density; disease phenotype; disorder risk; disorder subtype; early onset; functional genomics; gene interaction; genome wide association study; 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病。 MHC 以亚型特定方式涉及风险、易感性或保护，具有强烈的性别偏见和种族差异。多种 MHC 效应已被证实，特别是在最常见的亚型中，即所谓的早发性少关节 JRA（JIA 术语中的持续性寡核苷酸），其中三个或更多 MHC 区域被认为相互作用，产生易感性。与某些其他形式的自身免疫不同，该疾病的另一个特征是相对缺乏常见的延伸或祖先的免疫性疾病。 单倍型，特别是那些携带 HLA-DR4 和 HLA-DR7 的单倍型，这两者都具有保护性。这三个区域包括一个 I 类区域，或其端粒区域，以及两个 II 类区域，即 HLA DR/DQ 和 HLA-DP 周围的区域。所涉及的区域都没有明确定义，也没有确定所涉及的特定基因。标记这些区域的等位基因（HLA-DR8、11 和 HLA-DPB1*0201）对于自身免疫来说是非典型的。因此，这是 MHC 对自身免疫的不同寻常的贡献，其阐明有助于高通量技术的发展。尽管涉及关节炎，但其遗传特征与成人类风湿性关节炎有很大不同，除了约 5% 的年龄较大儿童外。建议在基于家族的研究中构建高通量 SNP 图谱。亚型具有不同的 MHC 特征，在最罕见和最严重的疾病（全身性 JRA）中，MHC 的影响相当小。在这种形式下，初​​步 涉及 KIR 基因单倍型的数据是可用的。建议对这些 KIR 基因进行观察。利用持续的表型分型和基于家族的样本收集的能力确保了该项目拥有大量且不断增长的可用 DMA。一些患者还将进行广泛的基因表达研究，以便对 JRA 及其亚型中的 MHC 和 KIR 基因进行全面的研究。