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在风险方面涉及以亚型的特定方式易感性或保护性，具有强烈的性别偏见和种族之间的差异。已经显示了多种MHC效应，尤其是在最常见的亚型中，所谓的早期发作pauciarticular Jra（JIA术语中的持续性寡核）具有三个或更多MHC区域，被认为在产生易感性时相互作用。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共同的延伸或祖先 单倍型，尤其是那些携带HLA-DR4和HLA-DR7的单倍型。这三个区域包括I类区域或端粒区域，以及两个II类区域，围绕HLA DR/DQ和HLA-DP的区域。所涉及的一个区域均未明确定义，也没有鉴定出涉及的特定基因。标记这些区域的等位基因（HLA-DR8，11和HLA-DPB1*0201）对于自身免疫性是非典型的。因此，这是对自身免疫性的不寻常的MHC贡献，其阐明将自己适合于高通量技术。遗传特征虽然涉及关节炎，但与成人类风湿关节炎完全不同，但约有5％的大儿童。提议在基于家庭的研究中构建高吞吐量SNP图。亚型具有不同的MHC谱，并且在最稀有，最严重的疾病形式，系统性发作JRA中，MHC效应相当小。以这种形式，初步 提供涉及KIR基因单倍型的数据。提出了追求这些KIR基因观察。利用正在进行的花序和基于家庭的样本收集的能力确保了该项目的大量可用DMA池。一些患者还将进行广泛的基因表达研究，允许对JRA及其亚型的MHC和KIR基因进行全面的方法。