RGD Reference Report - Identification of Two Novel Female-Specific Non-MHC Loci Regulating Collagen-Induced Arthritis Severity and Chronicity, and Evidence for Epistasis. - Rat Genome Database

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Identification of Two Novel Female-Specific Non-MHC Loci Regulating Collagen-Induced Arthritis Severity and Chronicity, and Evidence for Epistasis.

Authors: Meng, HC  Griffiths, MM  Remmers, EF  Kawahito, Y  Li, W  Neisa, R  Cannon, GW  Wilder, RL  Gulko PS.,  
Citation: Meng HC,etal., Arthritis Rheum. 2004 Aug;50(8):2695-705.
RGD ID: 1285224
Pubmed: (View Article at PubMed) PMID:15334486
DOI: Full-text: DOI:10.1002/art.20366

To identify additional sex-specific and epistatic quantitative trait loci (QTL) regulating collagen-induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex-identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant). METHODS: Arthritic male (DA x ACI)F2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis. All 327 rats were genotyped with the simple sequence-length polymorphism (SSLP) markers closest to the peak of Cia7 and Cia10, the major loci previously identified in this intercross, and with SSLPs covering chromosomes 12 and 18. Phenotypes studied were disease onset, arthritis severity scores on days 14-39, MAS, mean and cumulative arthritis scores, delayed-type hypersensitivity, and antibody responses to rat type II collagen. RESULTS: A new female-specific arthritis-severity recessive locus was identified on rat chromosome 12 (Cia25), with a maximum effect observed on day 28 (logarithm of odds [LOD] 4.7). The homozygous DA genotype at Cia25 was associated with a 45% higher median arthritis score in females. Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACI. The previously identified locus, Cia10, was found to be male-specific. A 2-locus interaction model analysis identified a novel recessive chromosome 18 QTL, Cia26, which was dependent on Cia7, with its maximum effect observed at later stages during the disease course (peak LOD score of 3.6 for arthritis scores on day 39). CONCLUSION: This study identified 2 novel female-specific loci, and 1 male-specific locus. Cia25 regulates MAS and disease severity during the mid-to-late stages of the disease course and may be accounted for by Ncf1 polymorphisms. Cia26 is in epistasis with Cia7 and regulates later stages of disease, suggesting an involvement in disease perpetuation and/or chronicity.

Annotation

Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

QTLs
Cia25  (Collagen induced arthritis QTL 25)
Cia26  (Collagen induced arthritis QTL 26)

Objects referenced in this article
Strain ACI/SegHsd null Rattus norvegicus
QTL Cia12 Collagen induced arthritis QTL 12 Rattus norvegicus
QTL Cia7 Collagen induced arthritis QTL 7 Rattus norvegicus
Strain DA/BklArbN null Rattus norvegicus
Gene Ncf1 neutrophil cytosolic factor 1 Rattus norvegicus

Additional Information