Fine Mapping of Collagen-Induced Arthritis Quantitative Trait Loci in an Advanced Intercross Line (original) (raw)
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Genes & Immunity, 2007
Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative trait loci (QTLs). Several AILs have been generated to refine QTLs since the method was proposed about a decade ago. However, no AIL has been used for identifying novel QTLs. Here we used an AIL to test this possibility. We genotyped 308 (DBA/1 Â FVB/N) F 11/12 AIL mice with 109 informative markers covering four chromosomes, with an average intermarker distance of 5.5 Mb. Several normally distributed quantitative traits involved in the immune response during the course of collagen-induced arthritis (CIA), such as anti-collagen II antibodies, T-cell subset proportions and reactive oxygen species (ROS) production were taken as phenotypes. Four QTLs, namely Ciaa1, Lctlp1, Lctlp2 and Rosq1, controlling anti-collagen II IgG2a levels, lymph nodes CD8 þ T cell proportion and ROS production were identified with support intervals of 15, 14, 8 and 8 Mb, respectively. Alleles of Lctlp1 and Lctlp2 suppressing CD8 þ T cell proportion as well as the Rosq1 allele enhancing ROS production were correlated with higher CIA severity scores. Taken together, we successfully used an AIL to identify novel QTLs controlling immune responses during CIA with relatively small support intervals.
Identification of new quantitative trait loci in mice with collagen-induced arthritis
Arthritis & Rheumatism, 2004
Objective. Collagen-induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models, with many features similar to rheumatoid arthritis. This study sought to identify potential genetic regulatory mechanisms of CIA in major histocompatibility complex-matched (H2-q) F 2 hybrid mice.
Human Molecular Genetics, 2011
Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F 2 crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred -outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2 q mice were then selected to set up an F 3 generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci.
Journal of immunology (Baltimore, Md. : 1950), 1999
The susceptibility to collagen-induced arthritis in the highly susceptible DBA/1 mouse has earlier been shown to be partly controlled by the MHC class II gene Aq. To identify susceptibility loci outside of MHC, we have made crosses between DBA/1 and the less susceptible B10.Q strain, both expressing the MHC class II gene Aq. Analysis of 224 F2 intercross mice with 170 microsatellite markers in a genome-wide scan suggested 4 quantitative trait loci controlling arthritis susceptibility located on chromosomes 6, 7, 8, and 10. The locus on chromosome 6 (Cia6), which was associated with arthritis onset, yielded a logarithm of odds score of 4.7 in the F2 intercross experiment and was reproduced in serial backcross experiments. Surprisingly, the DBA/1 allele had a recessive effect leading to a delay in arthritis onset. The suggestive loci on chromosomes 7 and 10 were associated with arthritis severity rather than onset, and another suggestive locus on chromosome 8 was most closely associat...
Genetic Control of Spontaneous Arthritis in a Four-Way Advanced Intercross Line
PLoS ONE, 2013
Identifying the genetic basis of complex diseases, such as rheumatoid arthritis, remains a challenge that requires experimental models to reduce the genetic and environmental variability. Numerous loci for arthritis have been identified in induced animal models; however, few spontaneous models have been genetically studied. Therefore, we generated a fourway advanced intercross line (AIL) from four inbred strains, including BXD2/TyJ which spontaneously develops autoimmune arthritis. A genome-wide scan for spontaneous arthritis was performed in a cohort of 366 mice of the fourth generation (G4) of this cross. Five loci contributing to clinical phenotypes were identified in chromosomes 3, 7, 13, 18, and X. Three of the loci found in this study, confirm previously identified loci; whereas two of them are novel loci. Interesting candidate genes for the loci are highlighted. This study provides a genetic overview of spontaneous arthritis in mice and aids to solve the genetic etiology of rheumatoid arthritis and to gain a better understanding of the disease.
Genetic and Molecular Basis of Quantitative Trait Loci of Arthritis in Rat: Genes and Polymorphisms
The Journal of Immunology, 2008
Rheumatoid arthritis (RA) is an autoimmune disease, the pathogenesis of which is affected by multiple genetic and environmental factors. To understand the genetic and molecular basis of RA, a large number of quantitative trait loci (QTL) that regulate experimental autoimmune arthritis have been identified using various rat models for RA. However, identifying the particular responsible genes within these QTL remains a major challenge. Using currently available genome data and gene annotation information, we systematically examined RA-associated genes and polymorphisms within and outside QTL over the whole rat genome. By the whole genome analysis of genes and polymorphisms, we found that there are significantly more RA-associated genes in QTL regions as contrasted with non-QTL regions. Further experimental studies are necessary to determine whether these known RA-associated genes or polymorphisms are genetic components causing the QTL effect.