1. Arthritis Rheum. 2004 Aug;50(8):2695-705.
Identification of two novel female-specific non-major histocompatibility complex
loci regulating collagen-induced arthritis severity and chronicity, and evidence
of epistasis.
Meng HC(1), Griffiths MM, Remmers EF, Kawahito Y, Li W, Neisa R, Cannon GW,
Wilder RL, Gulko PS.
Author information:
(1)North Shore-Long Island Jewish Research Institute, Manhasset, New York 11030,
USA.
OBJECTIVE: 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.
PMID: 15334486 [PubMed - indexed for MEDLINE]
PUBMED: 15334486
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