Murine collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis. CIA has been widely used to study the etiology, pathogenesis and new therapeutic approaches of rheumatoid arthritis. Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis. However, progress in identifying the new susceptibility genes outside the MHC locus has been slow. With the advent of new global methods for genetic analysis such as large-scale sequencing, gene expression profiling, combined with classical linkage analysis, congenic and physical and in silico fine mapping, progress is considerably accelerating. Here we present preliminary data using an integrative genomics strategy to identify new putative susceptibility genes contributing to the pathogenesis of CIA.
The strategy is based on integrating a genome scan to identify QTLs linked to clinical disease phenotypes and subtraits in a cross between the CIA-susceptible DBA1/J and resistant FVB/NJ mouse strains. Additionally, gene expression profiling in target tissues and immune cells in parental strains and their F2 progeny is performed. Numerous classical QTL and expression QTL were identified. Master QTLs/expression QTLs controlling basic disease traits and subtraits were selected for further analysis using in silico tools; for example, haplotype sharing analysis, interspecies synteny analysis, congenic mapping, and pathway construction.
So far we have confirmed C5 as a putative susceptibility gene for the Cia2 locus on chromosome 2. We also identified the mitochondrial ATP8 as a novel susceptibility gene. We are also pursuing three additional QTLs on chromosomes 1, 5, 18 controlling leukocyte–endothelial cell adhesion, anticollagen antibody production and arthritis severity. Functional analysis of candidate genes for those loci is underway.