Abstract
Previously, we identified a major quantitative trait locus (QTL) on mouse chromosome 1 that regulates the susceptibility to arthritis in an F2 population generated from arthritis-prone BALB/c and arthritis-resistant DBA/1 mice deficient for interleukin-1 receptor antagonist. To further select candidate genes for the QTL, we analyzed the expression patterns of arthritis in 38 F2 individuals and compared the expression levels of key candidate genes to the parental strains. Two distinct subpopulations of arthritic mice were identified in the 38 F2 mice. One subgroup of diseased mice was characterized by myeloid cell dominant inflammation, whereas the other was mainly associated with increased anti-apoptotic activities of inflammatory cells. Several differentially expressed important candidate genes in parental strains in the QTL region are relevant to myeloid cell, apoptotic activities, or to both. About one-quarter of those genes have been previously linked to arthritis in literature. The present study reveals two distinct subpopulations of arthritic mice with spontaneous arthritis due to deficiency for interleukin-1 receptor antagonist, suggesting that genes with function relevant to myeloid cell and/or apoptotic activities are most likely the key candidate genes for the QTL.
Highlights
Rheumatoid arthritis (RA), like other common polygenic autoimmune diseases, is characterized by genetic risk factor make-up and phenotypic heterogeneity
Using an F2 population generated from arthritis-prone BALB/c and arthritis-resistant DBA/1 mice deficient for interleukin-1 receptor antagonist (Il1rn), we identified a major quantitative trait locus (QTL) on mouse chromosome 1 that is responsible for about 12% of the susceptibility to spontaneous arthritis (Jiao et al, 2011)
Potential function in apoptotic and myeloid cells of key candidate genes in the QTL region In our previous study (Jiao et al, 2011), we found 11 genes (Mr1, Pla2g4a, Fasl, Prg4, Ptgs2, Tnfsf18, Tnfsf4, Rc3h1, Ncf2, Sell, and Selp) from the QTL region according to their differential expression
Summary
Rheumatoid arthritis (RA), like other common polygenic autoimmune diseases, is characterized by genetic risk factor make-up and phenotypic heterogeneity. Genetic polymorphisms of HLA genes, PTPN22, CTLA4, PADI4, FcγRs, and various cytokine and cytokine-receptor loci have been reported in different RA populations by linkage and association studies (McInnes and Schett, 2007). Fewer than half RA patients were positive in serum assays of the two most common RA markers, rheumatoid factors (RFs) (28%) and anticyclic citrullinated peptide (anti-CCP) antibodies (40%) at the time of diagnosis (van der Helm-van Mil et al, 2005). We sought to subclassify the population of autoimmune arthritic mice due to the deficiency of interleukin-1 receptor antagonist (Il1rn) based on their gene expression patterns
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