RGD Reference Report - Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains. - Rat Genome Database

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Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains.

Authors: Backdahl, L  Ribbhammar, U  Lorentzen, JC 
Citation: Backdahl L, etal., Arthritis Rheum 2003 Feb;48(2):551-9.
RGD ID: 629560
Pubmed: PMID:12571866   (View Abstract at PubMed)
DOI: DOI:10.1002/art.10782   (Journal Full-text)

OBJECTIVE: DA rats are highly susceptible to experimental models of rheumatoid arthritis (RA). Linkage analyses in different models have identified several quantitative trait loci (QTLs) within a 70-cM region of DA rat chromosome 4 (C4). We produced congenic strains for these QTLs in order to map and characterize their impact on arthritis development. METHODS: Selective breeding was used to transfer C4 intervals from arthritis-resistant PVG.1AV1 rats onto DA rats. These congenic strains were evaluated for susceptibility to arthritis induced by intradermal injection of rat type II collagen, pristane (a well-defined synthetic adjuvant oil), mycobacteria, or squalene (an endogenous adjuvant oil used in human vaccine). RESULTS: Rats congenic for PVG.1AV1 genes in the 70-cM region were less susceptible than DA rats to collagen-induced arthritis (CIA), pristane-induced arthritis, adjuvant-induced arthritis, and squalene-induced arthritis (SIA). Experiments in subcongenic strains indicated a gene regulating arthritis in males located in a 20-cM interval overlapping the QTL Pia5. A second gene, located in a 10-cM interval harboring the QTL Oia2, attenuated SIA and CIA. The latter caused a change in anticollagen antibody isotype levels toward a pattern similar to that seen in PVG.1AV1 rats. CONCLUSION: The QTL Oia2 regulates arthritis induced both by the nonimmunogenic immunostimulant squalene and by cartilage collagen. In CIA, it also skews anticollagen isotype profiles, suggesting qualitative regulation of autoimmunity. Interestingly, the homologous human chromosome region 12p12-p13 has also been linked to RA, suggesting that genetic and functional dissection of this locus will provide clues to disease pathways that lead to joint inflammation.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased susceptibility to induced arthritis penetranceIAGPpristane or squalene or type II collagen and Freund's incomplete adjuvant or Freund's complete adjuvant629560compared to DA/ZtmKiniRGD 
increased IgG1 level  IAGPtype II collagen and Freund's incomplete adjuvant629560compared to DA/ZtmKiniRGD 
increased IgG2b level  IAGPtype II collagen and Freund's incomplete adjuvant629560; 629560compared to DA/ZtmKiniRGD 
increased IgG2c level  IAGPtype II collagen and Freund's incomplete adjuvant629560compared to DA/ZtmKiniRGD 
increased susceptibility to induced arthritis  IAGPtype II collagen and Freund's incomplete adjuvant629560compared to PVG.1AV1/KiniRGD 
increased susceptibility to induced arthritis  IAGPpristane or type II collagen and Freund's incomplete adjuvant629560compared to PVG.1AV1/KiniRGD 
increased susceptibility to induced arthritis  IAGPtype II collagen and Freund's incomplete adjuvant or pristane or squalene629560compared to PVG.1AV1/KiniRGD 
increased susceptibility to induced arthritis penetranceIAGPpristane or squalene or type II collagen and Freund's incomplete adjuvant or Freund's complete adjuvant629560compared to control strain PVG.1AV1RGD 
increased susceptibility to induced arthritis  IAGPpristane or squalene or type II collagen and Freund's incomplete adjuvant or Freund's complete adjuvant629560compared to control strain PVG.1AV1/KiniRGD 
joint inflammation sexual_dimorphismIAGPtype II collagen and Freund's incomplete adjuvant629560in males and compared to DA/ZtmKiniRGD 
joint inflammation penetranceIAGPsqualene or pristane or Freund's complete adjuvant or type II collagen and Freund's incomplete adjuvant629560compared to DA/ZtmKiniRGD 
joint inflammation susceptibilityIAGPpristane629560compared to PVG.1AV1/KiniRGD 
joint inflammation severityIAGPsqualene or type II collagen and Freund's incomplete adjuvant629560compared to DA/ZtmKiniRGD 
joint inflammation susceptibilityIAGPpristane or squalene or type II collagen and Freund's incomplete adjuvant or Freund's complete adjuvant629560compared to control strain PVG.1AV1/KiniRGD 
joint inflammation  IAGP 629560; 629560; 629560; 629560 RGD 
joint inflammation penetranceIAGPtype II collagen and Freund's incomplete adjuvant or pristane629560 RGD 
weight loss sexual_dimorphismIAGPtype II collagen and Freund's incomplete adjuvant629560in males and compared to DA/ZtmKiniRGD 
weight loss  IAGPFreund's complete adjuvant or squalene629560compared to PVG.1AV1/KiniRGD 
weight loss  IAGPtype II collagen and Freund's incomplete adjuvant or pristane629560compared to PVG.1AV1/KiniRGD 
weight loss severityIAGPFreund's incomplete adjuvant and type II collagen629560compared to DA/ZtmKiniRGD 
weight loss susceptibilityIAGPpristane or squalene or type II collagen and Freund's incomplete adjuvant or Freund's complete adjuvant629560compared to control strain PVG.1AV1/KiniRGD 

Objects Annotated

QTLs
Oia8  (Oil induced arthritis QTL 8)
Pia22  (Pristane induced arthritis QTL 22)
Pia7  (Pristane induced arthritis QTL 7)
Pia9  (Pristane induced arthritis QTL 9)

Objects referenced in this article
QTL RA20_H Rheumatoid arthritis QTL 20 (human) Homo sapiens
QTL Aia2 Adjuvant induced arthritis QTL 2 Rattus norvegicus
QTL Aia3 Adjuvant induced arthritis QTL 3 Rattus norvegicus
QTL Aia5 Adjuvant induced arthritis QTL 5 Rattus norvegicus
QTL Cia13 Collagen induced arthritis QTL 13 Rattus norvegicus
QTL Cia3 Collagen induced arthritis QTL 3 Rattus norvegicus
Strain DA DA Rattus norvegicus
QTL Oia2 Oil induced arthritis QTL 2 Rattus norvegicus
QTL Pia5 Pristane induced arthritis QTL 5 Rattus norvegicus
Strain PVG.1AV1 Piebald-Virol-Glaxo Rattus norvegicus

Additional Information