MAPPING OF ARTHRITIS SUSCEPTIBILITY GENES

与MHC（主要组织相容性复合体）的强关联是人类自身免疫性疾病（包括类风湿性关节炎（RA））的最重要的已知遗传易感因素。然而，单独的MHC似乎不足以诱导多基因自身免疫性疾病，因为非MHC连锁的遗传因素控制疾病的易感性、严重性或其他临床和免疫学特征。蛋白聚糖诱导的关节炎（PGIA）是一种新型的自身免疫性动物模型，它与类风湿性关节炎（RA）有许多相似之处，包括全身和局部炎症反应以及遗传学。在目前的项目期间，我们对五种不同的F2杂交小鼠（包括665只关节炎小鼠）进行了基因组扫描。 每个杂交使用超过150个简单序列长度多态性（SSLP）标记进行遗传杂交。作为这些全基因组筛选研究的结果，我们已经确定了总共29个遗传基因座（Pgia）与PGIA，和15个数量性状基因座（QTL）与胶原诱导的关节炎（CIA）在小鼠（mCia）。许多关节炎相关的临床和免疫QTL共享染色体区域，在PGIA和CIA中是常见的，并且与其他自身免疫模型及其相应的人类疾病的QTL共定位。在这个项目的延续中，我们建议（i）进行基因组筛选和鉴定 在两个遗传上（几乎）相同的鼠亚群（C3 H/HeJ vs.C3H/HeJCr）中可能存在单个关节炎易感性基因座，（ii）使用同源系和亚同源系选择最关键的遗传基因座（QTL），和（iii）减小所选染色体区域的大小以适合于定位候选基因克隆。潜在地，可以将关节炎易感亲本菌株和受疾病影响的F2杂种中的候选基因的序列与关节炎抗性菌株和/或个体中的相应序列进行比较。

A strong association with the MHC (major histocompatibility complex) is the most important known genetic predisposition factor of human autoimmune diseases, including rheumatoid arthritis (RA). The MHC alone, however, seems to be insufficient for the induction of a polygenic autoimmune disease, because non-MHC-linked genetic factors control susceptibility, severity, or other clinical and immunological traits of the disease. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a novel autoimmune animal model which shares many similarities with RA, including systemic and local inflammatory reactions and genetics. During the current project period, we have genome-scanned over 2,200 F2 hybrid (including 665 arthritic) mice of five different genetic intercrosses using over 150 simple sequence length polymorphic (SSLP) markers for each cross. As a result of these genome-wide screening studies, we have identified a total of 29 genetic loci (Pgia) linked to PGIA, and 15 quantitative trait loci (QTLs) linked to collagen-induced arthritis (CIA) in mice (mCia). Many of the arthritis-associated clinical and immunological QTLs shared chromosome regions, being common in both PGIA and CIA, and co-localized with QTLs of other autoimmune models and their corresponding human diseases. In the continuation of this project we propose to (i) perform genome screening and identify possibly a single arthritis susceptibility locus in two, genetically (almost) identical, murine subcolonies (C3H/HeJ vs. C3H/HeJCr), (ii) select the most critical genetic loci (QTLs) using congenic and sub-congenic lines, and (iii) reduce the size of selected chromosomal regions to be suitable for positional candidate gene cloning. Potentially, sequences of candidate genes in arthritis-susceptible parental strains and disease-affected F2 hybrids can be compared with corresponding sequences in arthritis-resistant strains and/or individuals.