Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis

Abstract

Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/ 2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (~3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.

Non-MHC Risk Alleles in Rheumatoid Arthritis and in the Syntenic Chromosome Regions of Corresponding Animal Models

“…During the past 15 years, we and others have identified 29 Pgia and 40 Cia loci in different genetic combinations of F2 hybrid mice [3, 10, 11, 57, 58, 82, 86, 95–99] and a couple of corresponding QTLs in rats [100–105]. With a strong confirmation in the literature, we selected QTLs from all (published) mouse genomic studies [10, 56–58, 82–84, 92–96, 98, 106–112] that also correspond to one of the major risk loci of RA confirmed in a number of meta-analyses [19, 29, 90, 113–117]. Table 1 summarises the risk alleles selected that have corresponding genomic regions from human and mouse GWAS.…”

“…For example (Figure 1), the “Chr3G0” (“3G0”) subcongenic line contains an overlapping region ~66 Mbp in size that significantly affected all clinical phenotypes when compared to either susceptible BALB/c or resistant DBA/2 parental strains [84], a finding that needs to be further confirmed by in vitro tests (i.e., measuring biomarkers). In this case, males from the congenic 3G0 strain can be used to reduce the chromosome interval with new recombination events with matings into inbred BALB/c females.…”

“…As shown in Figures 2(a) and 2(b) and Table 1, the PTPN22/CD2 human risk locus most likely represents a complex trait on mChr3 (syntenic with hChr1) containing both disease-suppressive and disease-promoting alleles [84]. Distinct regions, alone or in combination, may result in clinically similar phenotypes (Figure 1), while the IVSC-associated biomarkers may show significant differences.…”

“…All other congenic and subcongenic strains were cryopreserved. The two major/dominant mouse QTLs were separated into narrow subtraits and simultaneously tested for arthritis susceptibility, for disease onset and severity, and for over 15 biomarkers that might have some potential relevance for RA [84]. Simultaneously, some of the IVSC genomic regions representing homogeneous regions of disease-susceptible and disease-resistant IVSC mice (and the corresponding parent genomic regions) were sequenced, and a few mutated genes were identified (with “known” or completely unknown function).…”

“…Horizontal black lines with numbers at the right side (and with marker names) are shown. The short red lines crossing the IVSC chromosome region indicate the position between the two markers, where the DBA/2 allele continued as BALB/c [84]. The blue-framed red rectangular area indicates the position of the Pgia26d locus (between 101.4 and 107.2 Mbp); in the worst case, this region may include the entire flanking region between 99.9 and 108.8 Mbp where the disease-promoting gene(s) in BALB/c mice is located (or reciprocally, the suppressive genes in DBA/2).…”