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

Abstract

Objective.To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type I1 collagen-induced arthritis (CIA).Methods. We conducted a genome-wide scan to identify CLA regulatory quantitative trait loci (QTL) in an F, cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type I1 collagen (MI). These strains share the MHC/RTlaV1 haplotype required for susceptibility to RII-induced CIA.Results. F, 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 diabe-

Genetic links between the acute-phase response and arthritis development in rats

“…Many of the identified loci that showed a significant LOD score (Ͼ3.4) (27) were in the same chromosomal regions as previously published arthritis QTLs in rats (30,(32)(33)(34)(35). The previously identified locus on chromosome 12 (Pia4) (30), which controls erosive arthritis, was found also to be associated with elevated serum levels of ␣ 1 -acid glycoprotein on day 14 (LOD 6.0 in males only) and IL-6 on day 35 (LOD 6.7 in males only).…”

“…The plasma was separated from blood cells by centrifugation and stored at Ϫ70°C until assayed. Plasma from parental strains was collected on days 0, 4,8,12,16,20,25,30,35,42,49,60,80, 100, 120, and 150 after pristane injection. Serum was collected from the (E3 ϫ DA)F 2 rats on days 14, 35, 49, and 100.…”

“…The chromosome 14 locus (Pia6), associated with chronic arthritis was found to be associated with elevated IL-6 levels as early as day 14 after pristane injection. Another locus associated with elevated IL-6 levels (on day 49) was found to be located on chromosome 10, close to the Oia3/Cia5 locus associated with oil-induced arthritis and collagen-induced arthritis in crosses involving strains other than E3 (34,35).…”

Identification of Rat Quantitative Trait Loci that Regulate LPS‐Induced Pro‐Inflammatory Cytokine Responses

“…In addition, the IL-6 analysis identified a genomewide significant QTL on chr.2 that colocalizes with a possible TNF-a QTL. The identified QTLs on chr.1 and chr.2 overlap with arthritis-regulating QTLs [23,24]. This suggests that the described genetic dissection of in vitro phenotypes represents a novel way to identify genes that regulate physiologic and pathogenic in vivo responses to arthritogenic adjuvant, such as LPS.…”

DA rats from two colonies differ genetically and in their arthritis susceptibility

“…The DA rat has a leading role in the search for arthritis-susceptible genes. Worldwide four different institutes have reported linkage studies with collagen II-induced arthritis that were performed using the arthritissusceptible DA strain in combination with various resistant rat strains such as ACI, BN, E3, and F344 (Dracheva et al 1999;Griffiths et al 2000;Gulko et al 1998;Meng et al 2004;Olofsson et al 2003b;Remmers et al 1996). These (a) Arthritis incidence in DA/OlaHsd (n = 55) and DA/ZtmRhd (n = 54) rats after a 50-ll pristane injection.…”