Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22–q25 locus

Abstract

Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA Â 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.

Advanced Intercross Line Mapping Suggests That Ncf1 (Ean6) Regulates Severity in an Animal Model of Guillain-Barré Syndrome

“…We identified five QTLs overlapping already described loci for the chronic inflammatory and thus EAN-related models EAE and EA (17,19,(27)(28)(29). This indicates a number of shared mechanisms between these complex inflammatory disease models converging at common inflammatory key events, despite their differences in etiology.…”

Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case-control association data

“…In the present study we describe results of an alternative method. We aimed to define candidate risk genes in regions on Rattus norvegicus chomosome 4 and 10 (RNO4 and 10) that influence experimental RA,10 11 12 13 14 15 16 and in the corresponding human chromosome regions which link to, and associate with, RA 17 18 19. As well as RA, the targeted regions also associate with other inflammatory diseases, and there is evidence for more than one risk gene in each region 20 21 22 23 24 25 26 27 28 29 30 31 32 33…”

The arthritis severity quantitative trait locus Cia7 regulates neutrophil migration into inflammatory sites

“…DA.ACI(Cia10), DA.ACI(Cia25) and DA.ACI(Cia27) homozygous congenics were generated as described previously 18,19 ( Figure 1). Briefly, each interval of interest was introgressed from ACI into the DA genetic background through eight to 10 genotypeguided backcrosses followed by at least five intercrosses.…”

“…Several non-major histocompatibility complex (MHC) arthritis severity quantitative trait loci (QTL) were previously identified in a F2 intercross between arthritis-susceptible DA and MHC-identical but arthritisresistant ACI rats, 16,17 and their arthritis regulatory effect confirmed in DA.ACI(QTL) congenic strains 18,19 (Brenner et al, unpublished observations). We postulated that part of the difference in arthritis susceptibility and severity between DA and ACI could be accounted for by differences in the genetic regulation of neutrophil migration into the inflammatory synovial cavity.…”