Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen‐induced arthritis

Abstract

Objective. Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats.Methods. Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA ؋ BN)F 2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay.Results. DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA ؋ BN)F 1 rats (7 of 60) and 31% of (DA ؋ BN)F 2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA ؋ F344) and (DA ؋ ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA ؋ BN)F 2 rats.Conclusion. Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.

A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

“…This arthritis-regulating locus overlaps with the previously reported Cia11 locus, which was identified in experiments using DA and BN rats (20). Other significant loci that regulate clinical arthritis have previously been reported, as follows: on chromosome 4, Cia3/Pia5 and Cia13/Pia7, on chromosome 6, Cia20/Pia3, and on chromosome 12, Cia12/Pia4 (Table 2 and Figure 1A).…”

“…With regard to CIA in rats, most linkage analyses have been performed in the setting of bovine CIIinduced arthritis and in strain combinations other than E3 with DA (19)(20)(21)(22)(23). Therefore, in order to make a reasonable comparison of the genetic inheritance of CIA and PIA in rats, we performed linkage analysis of CIA in the same strain combination and induced by the same collagen source that was used for the PIA studies.…”

Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis

“…39 Pia4 also colocalises with other QTLs for autoimmune disease, for example, Eae5, Eau2 and Cia12. 26,40,41 In a region on mouse chromosome 5, which is homologous to Pia4, association has been reported to arthritis severity of Lyme disease. 42 These findings indicate that common susceptibility genes for several autoimmune diseases exist.…”

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

“…Studies in rodent intercrosses identified several arthritis susceptibility, severity and chronicity loci (Table 1). 29,[32][33][34][35][36][37][38][39][40][41][42][43][44][45] The RA genome-wide family-based genetic studies were not designed or structured to address disease severity, histologic damage or the other arthritis-related phenotypes that can be studied in rodents. More recent cohorts have been incorporating severity and outcome parameters in their prospective data collection and will likely have a major role in RA severity genetic association studies.…”