A genome scan localizes five non–MHC loci controlling collagen–induced arthritis in rats

Remmers, Elaine F.; Longman, Ryan E.; Du, Ying; O’Hare, Ann M.; Cannon, Grant W.; Griffiths, Marie; Wilder, Ronald L.

doi:10.1038/ng0996-82

Cited by 194 publications

(151 citation statements)

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“…Amd1 and Asm1 may be a common locus for the same etiology of these 2 kinds of diseases. This is also the first study to map a gene locus for susceptibility to spontaneous arthropathy in DBA/1 mice, Amd2, on chromosome 3 in the region of a DBA/1 (14,22) and other mouse and rat models (23)(24)(25). However, the region of Amd2 did not share any of the loci involving the MHC.…”

Section: Discussionmentioning

confidence: 85%

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Oishi¹,

Miyazaki²,

Mizuki³

et al. 2005

Arthritis & Rheumatism

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Objective. To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy.Methods. MRL, DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0-3 and 0-5 scale, respectively). A genome-wide scan of 271 male F 2 intercross mice with polymorphic microsatellite markers was performed.Results. Only male DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F 2 mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F 2 mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy.Conclusion. Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/ MpJ-lpr/lpr mice.

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Section: Discussionmentioning

confidence: 85%

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Oishi¹,

Miyazaki²,

Mizuki³

et al. 2005

Arthritis & Rheumatism

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“…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.…”

mentioning

confidence: 99%

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

Olofsson¹,

Lu²,

Holmberg³

et al. 2003

Arthritis & Rheumatism

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Objective. To compare the genetic regulation of collagen-induced arthritis (CIA) with that of pristaneinduced arthritis (PIA) in rats.Methods. A genome-wide linkage analysis of an (E3 ؋ DA)DA backcross of rats with CIA (n ‫؍‬ 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA.Results. We found a striking, although not complete, similarity of the arthritis-controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute-phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity.Conclusion. The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA.

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“…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.…”

Section: Inducible Modelsmentioning

confidence: 99%

“…For example, DA Â F344 F2 intercrosses studied for CIA identified six non-MHC loci, 40,43 while the same intercross studied for AIA led to the identification of only three non-MHC loci. Of these, only one non-MHC locus, Cia3/Aia3, was common to both models, while the others were model specific.…”

Section: Spontaneous Modelsmentioning

confidence: 99%

“…79 Large rodent offspring generated in experimental intercrosses facilitated the identification of epistatic loci outside the MHC (Cia7 with Cia26) 80 and between MHC and non-MHC CIA and AIA loci. [40][41][42] Furthermore, studies in advanced intercross lines, 72,81 bi-congenic 82 and subcongenic strains 31 identified interacting loci in different chromosomes or within the same chromosome. Therefore, epistatic interactions and their functional characterization can be more easily and convincingly characterized in rodents and subsequently tested in RA in a gene-gene specific manner.…”

Section: Advanced Intercross Lines To Refine Arthritis Qtl Intervalsmentioning

confidence: 99%

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

Gulko

2007

Genes Immun

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Rheumatoid arthritis (RA) is a chronic and potentially debilitating autoimmune disease. While novel therapies have emerged in recent years, disease remission is rarely achieved. RA is a complex trait, and the identifying of its susceptibility and severity genes has been anticipated to generate new targets for therapeutic intervention. However, finding those genes and understanding their function has been a challenging task. Studies in rodent intercrosses and congenics generated from inbred strains have been an important complementary strategy to identify arthritis genes, and understand how they operate to regulate disease. Furthermore, these new rodent arthritis genes will be new targets for therapeutic interventions, and will identify new candidate genes or candidate pathways for association studies in RA. In this review-opinion article I discuss RA genetics, difficulties involved in gene identification, and how rodent models can facilitate (1) the discovery of both arthritis susceptibility and severity genes, (2) studies of gene-environment interactions, (3) studies of gene-gender interactions, (4) epistasis, (5) functional characterization of the specific genes, (6) development of novel therapies and (7) how the information generated from rodent studies will be useful to understanding and potentially treating RA.

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A genome scan localizes five non–MHC loci controlling collagen–induced arthritis in rats

Cited by 194 publications

References 28 publications

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

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

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

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