Brenner M, Laragione T, Yarlett N C, Li W, Mello A, Gulko P S
Laboratory of Experimental Rheumatology, The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY 11030, USA.
Genes Immun. 2006 Jul;7(5):335-41. doi: 10.1038/sj.gene.6364304. Epub 2006 May 4.
Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA x ACI) F2. As an initial step towards the positional cloning of the Cia27 gene, a 17 cM (21 Mb) interval from the DA strain (arthritis-susceptible) containing the two-logarithm of odds support interval comprising Cia27 was introgressed into the ACI (arthritis-resistant) background through genotype-guided congenic breeding. ACI.DA(Cia27) congenics developed a significantly more severe form of arthritis (CIA), with a 5.9-fold increase in median arthritis severity index, a parameter known to correlate with synovial inflammation, and cartilage and bone erosions, compared with ACI (P< or =0.001). The arthritis severity enhancing effect could be detected from day 21 onwards. Rats heterozygous at the congenic interval developed a disease similar to ACI rats, suggesting that DA alleles operate in a recessive manner. Levels of autoantibodies anti-rat type II collagen did not correlate with arthritis severity. Synovial tissue mRNA levels of interleukin-1beta (IL-1beta) were significantly increased in ACI.DA(Cia27) congenics compared with ACI. These results demonstrate that Cia27 harbors a novel arthritis severity regulatory gene. The identification of this gene should facilitate the identification of the rheumatoid arthritis gene mapped to the human syntenic region on chromosome 17q22-q25.
大鼠10号染色体上的Cia27是一个胶原诱导性关节炎（CIA）严重程度数量性状位点，最初是在一项（DA×ACI）F2研究中发现的。作为对Cia27基因进行定位克隆的第一步，通过基因型引导的同源近交系培育，将来自DA品系（关节炎易感）的一个17厘摩（21兆碱基）区间（包含包含Cia27的两倍对数优势支持区间）导入到ACI（关节炎抗性）背景中。与ACI相比，ACI.DA（Cia27）同源近交系发生了明显更严重的关节炎（CIA）形式，中位关节炎严重程度指数增加了5.9倍，该参数已知与滑膜炎症以及软骨和骨侵蚀相关（P≤0.001）。从第21天起就可以检测到关节炎严重程度增强效应。在同源区间杂合的大鼠发生了与ACI大鼠相似的疾病，这表明DA等位基因以隐性方式起作用。抗大鼠II型胶原自身抗体水平与关节炎严重程度无关。与ACI相比，ACI.DA（Cia27）同源近交系滑膜组织中白细胞介素-1β（IL-1β）的mRNA水平显著升高。这些结果表明，Cia27含有一个新的关节炎严重程度调节基因。该基因的鉴定应有助于鉴定定位于人类17q22 - q25同区域的类风湿关节炎基因。
