Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis

Abstract

B10.RIII mice develop chronic and relapsing experimental autoimmune encephalomyelitis (EAE) after immunization with the myelin basic protein (MBP) peptide 89-101. The disease is associated with the major histocompatibility complex (MHC) (eae1). We have now investigated the importance of non-MHC regions for the EAE susceptibility in a cross between RIIIS/J and B10.RIII mice which share the MHC region but differ in disease susceptibility. Linkage analysis using microsatellite markers spanning the genome identified a region (eae2) on chromosome 15 which showed linkage to disease (P = 0.0002). Our data also suggest linkage to a second region (eae3) on chromosome 3 (P = 0.0024), and provide evidence for locus interactions between eae2 and eae3. These results provide clues to the genetic basis of multiple sclerosis.

Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice

“…We chose to use the R/qtl software 22 to analyze genetic interactions. By using R/qtl on the original F2 intercross data, 13 we were able to verify the finding that the main genetic interaction occurred between Eae3 on chromosome 3 and Eae2 on chromosome 15 (data not shown). Owing to the way the PAI was created, there was however a risk in utilizing a multipoint analysis.…”

“…We have found the original Cia5/Eae3 locus 13,14 to consist of three loci affecting separate phases of the progression of arthritis, which each interacted uniquely with loci on chromosome 15. Cia5 affects disease onset and early severity, whereas Cia21 and Cia22 affect the chronic/late phase of the disease.…”

“…Data from the previous EAE experiment on an F2 intercross between the B10.RIII and RIIIS/J mouse strains indicated an interaction between Eae3 on chromosome 3 and the Eae2 locus on chromosome 15. 13 To define the interactions and isolate the underlying genes into smaller fragments we created a PAI between Eae2 and Cia5/Eae3 congenic strains. This was done by selectively intercrossing mice with recombinations within Cia5/Eae3 and Eae2 for eight generations.…”

“…Mice were examined for clinical signs of EAE based on an eight score scale as described previously. 13 Genotyping Genomic DNA was isolated from 1 mm tail or toe. The samples were dissolved in 500 ml 50 mM NaOH, in 951C for 1-2 h, and then 100 ml 1 mM Tris buffer (pH 8) was added.…”

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene

“…Since we previously observed that genotypes homozygous for the short GA 13 and GA 16 alleles or heterozygous GA 13 /GA 16 were associated to MS, we specifically examined these three genotypes in JRA patients. As can be seen from Figure 2, all the three genotypes were increased among the JRA patients, but only the heterozygous GA [13][14][15][16] genotype reached statistical significance (5% vs 1%; OR ¼ 3.9; 95% CI (1.4-11.6); P n ¼ 4 ¼ 0.036). Overall, JRA patients carried significantly more frequent two copies of 'short' alleles (GA 13 and/or GA 16 ) compared to healthy controls (10% vs 6%; OR ¼ 1.9; 95% CI (1.1-3.5); P n ¼ 2 ¼ 0.04).…”