Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen-induced arthritis in rats

Objective. To identify novel non-major histocompatibility complex (non- MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA). Methods. We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F₂ cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1(av1) haplotype required for susceptibility to RII-induced CIA. Results. F₂ females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. In addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans. Conclusion. Sex chromosomes and Cia7 play an important role in regulating CIA in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis.