ORIGINAL ARTICLE Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22–q25 locus M Brenner, T Laragione, NC Yarlett, W Li, A Mello and PS Gulko 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, USA Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA  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 (Pp0.001). 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-1b (IL-1b) 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. Genes and Immunity (2006) 7, 335–341. doi:10.1038/sj.gene.6364304; published online 4 May 2006 Keywords: autoimmunity; inflammation; genetic; quantitative trait Introduction Rheumatoid arthritis (RA) is a complex trait with a strong genetic component that affects 0.5–1% of the population. 1,2 Several major histocompatability complex (MHC) and non-MHC susceptibility loci 3–7 have been recently mapped and a few of their respective genes 8–10 have been identified. However, the identity of most susceptibility genes remains largely unknown. Among the difficulties involved in gene identification are the inherent characteristics of complex traits, which include variable penetrance, variable relative risk associated with the disease allele and epistasis, and the genetic hetero- geneity of human populations. 11 Additionally, yet uni- dentified sex factors appear to regulate the penetrance of certain arthritis-regulatory alleles, making some disease alleles sex-specific. 12–17 Little is known about the genetic regulation of disease severity and none of the RA multi-institutional family- based genome-wide screens was designed to address disease severity. These severity genes could have a more significant role in the perpetuation (chronicity) of the inflammatory process and joint damage, and thus could generate better targets for drug development. Studies of rodent models of arthritis in intercrosses generated with inbred strains that differ in their susceptibility to and severity of disease can overcome several difficulties involved in complex trait analyses, thus having the potential to facilitate gene identifica- tion. 11,18 Once identified, these rodent arthritis genes will provide novel targets for focused candidate gene, or candidate pathway analysis in RA case–control studies. In order to identify non-MHC loci regulating disease severity in collagen-induced arthritis (CIA), an F2 intercross was generated between MHC RT1 av1 identical DA (arthritis-susceptible) and ACI (arthritis-resistant) strains. Five non-MHC arthritis regulatory quantitative trait loci (QTL), and a major gender effect were identified. 16,19 One of these loci, named Cia27 in the present study, reached a maximum logarithm of odds (LOD) score of 2.6 closest to D10Wox7, 19 and raised great interest because of its location in a region of rat chromosome 10 implicated in the regulation of several autoimmunity phenotypes and diseases, 20,21 including arthritis in rodents 22–24 and humans. 4,25 Therefore, as a second step towards identification of the gene account- ing for Cia27, we report here that ACI.DA(Cia27) congenic rats were generated and studied for their susceptibility to and severity of autoimmune arthritis Received 21 February 2006; revised 21 March 2006; accepted 21 March 2006; published online 4 May 2006 Correspondence: Dr PS Gulko, Laboratory of Experimental Rheu- matology, The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research at North Shore- LIJ, 350 Community Drive, room 139, Manhasset, NY 11030, USA. E-mail: pgulko@nshs.edu Genes and Immunity (2006) 7, 335–341 & 2006 Nature Publishing Group All rights reserved 1466-4879/06 $30.00 www.nature.com/gene