HLA/KIR Region Genetics in Pediatric Arthritis

小儿关节炎中的 HLA/KIR 区域遗传学

• 批准号: 7008022
• 负责人: DAVID N. GLASS
• 金额: $ 21.03万
• 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/7008022
• 关键词: adolescence (12-20); cell surface receptors; child (0-11); clinical research; cooperative study; family genetics; gene expression; genetic mapping; genetic susceptibility; high throughput technology; human genetic material tag; human subject; juvenile rheumatoid arthritis; major histocompatibility complex; natural killer cells; single nucleotide polymorphism

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）包括儿童期最常见的慢性自身免疫性关节病。MHC以亚型特异性方式参与风险、易感性或保护，具有强烈的性别偏见和种族差异。已显示出多种MHC效应，尤其是在最常见的亚型中，即所谓的早发性少关节JRA（JIA术语中的持续寡聚物），其中三个或更多MHC区域据信在产生易感性方面相互作用。与其他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延伸或祖先免疫。 单倍型，特别是携带HLA-DR 4和HLA-DR 7的那些，这两种单倍型都是保护性的。这三个区域包括一个I类区域或与之端粒相连的区域，以及两个围绕HLA DR/DQ和HLA-DP的II类区域。所涉及的区域都没有很好的定义，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-DR 8，11和HLA-DPB 1 *0201）对于自身免疫是非典型的。因此，这是一个不寻常的MHC自身免疫的贡献，其阐明本身的高通量技术。遗传特征，虽然涉及关节炎，是相当不同于成人类风湿性关节炎除了约5%的年龄较大的儿童。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谱，并且在最罕见和最严重的疾病形式中，全身性发作的JRA，MHC效应相当小。在这种情况下，初步 涉及KIR基因单倍型的数据是可用的。追求这些KIR基因的意见提出。利用正在进行的表型分析和基于家族的样本收集的能力确保了该项目的可用DMA的大型且不断增长的池。一些患者还将进行广泛的基因表达研究，以便全面了解JRA及其亚型中的MHC和KIR基因。