Genetic dissection of collagen-induced arthritis in Chromosome 10 quantitative trait locus speed congenic rats: evidence for more than one regulatorylocus and sex influences

Rat Chromosome 10 (RNO10) harbors Cia5, a non-MHC quantitative trait locus (QTL) that regulates the severity of type II collagen-induced arthritis (CI A) in DAxF344 and DAxBN F2 rats. CIA is an animal model with many features that resemble rheumatoid arthritis. To facilitate analysis of Cia5 independ ently of the other CIA regulatory loci on other chromosomes, DA recombinant QTL speed congenic rats, DA.F344(Cia5), were generated. These QTL congenic rats have a large chromosomal segment containing Cia5 (interval size less than or equal to 80.1 cM) from CIA-resistant F344 rats introgressed into th eir genome. Phenotypic analyses of these rats for susceptibility and severi ty of CIA confirmed that Cia5 is an important disease-modifying locus. CIA severity was significantly lower in the Cia5 congenic rats than in DA contr ols. We also generated DA Cia5 speed sub-congenic rats, DA.F344(Cia5a), whi ch had a smaller segment of the F344 genome, Cia5a, comprising only the dis tal q-telomeric end (interval size less than or equal to 22.5 cM) of Cia5, introgressed into their genome, DA,F344(Cia5a) sub-congenic rats also exhib ited reduced CIA disease severity compared with the parental DA rats, The r egulatory effects in both congenic strains were sex influenced. The disease -ameliorating effect of the larger fragment, Cia5, was greater in males tha n in females, but the effect of the smaller fragment, Cia5a, was greater in females. We also present an improved genetic linkage map covering the Cia5 /Cia5a region, which we have integrated with two rat radiation hybrid maps. Comparative homology analysis of this genomic region with mouse and human chromosomes was also undertaken. Regulatory loci for multiple autoimmune/in flammatory diseases in rats (RNO10), mice (MMU11), and humans (HSA17 and HS A5q23-q31) map to chromosomal segments homologous to Cia5 and Cia5a.