Cia5^RIIIS/J
QTL Variant Detail

Summary

• QTL variant: Cia5^RIIIS/J
• Name: collagen induced arthritis QTL 5; RIIIS/J
• MGI ID: MGI:2155398
• QTL: Cia5 Location: Chr3:83046658-83046795 bp Genetic Position: Chr3, cM position of peak correlated region/allele: 37.01 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: RIIIS/J

Variant description

• Allele Type: QTL
• Inheritance: Dominant

Notes

Cia5 interacts with Cia31, Cia30, and Cia32 on mouse Chromosome 15.

Heterozygosity at Cia31 and RIIIS/J-derived alleles at Cia5 confers delayed onset of collagen-induced arthritis in female animals with an additive effect.

Interaction between Cia5 and Cia32 affects arthritis severity in the early and late phases of disease in both male and female animals.

Interaction between Cia5 and Cia30 affects arthritis severity in the late phase of disease in both male and female animals.

Candidate Genes

J:81372

Microarray gene expression analysis was used to identify candidate genes for QTLs associated with collagen-induced arthritis. RNA from inflamed paws of collagen-treated mice were used in the microarray analysis and compared to RNA from normal paws. 223 genes showed a four-fold or greater expression difference between inflamed and normal paws. Nine of these genes are located near previously identified arthritis severity/susceptibility QTLs and may be considered for candidates.

For Cia1 on mouse Chromosome 17 (18.6 cM near the H2 locus) differential expression was observed for H2-Eb1 (18.66 cM) and H2-T23 (19.73 cM).

For Cia2 and Cia4 on mouse Chromosome 2 (both are located at 34 cM) differential expression was observed for Fap (36 cM) and Gcg (36 cM).

For Cia3 (48.7 cM) and Cia6 (30 cM) on mouse Chromosome 6 differential expression was observed for Raf1 (52.5 cM) and Slc6a6 (38.2 cM), respectively.

For Cia5 (40 cM) on mouse Chromosome 4 differential expression was observed for Ctsk (47.9 cM) and Cd53(50.5 cM).

For Cia8 (40.4 cM) on mouse Chromosome 10 differential expression was observed for Bsg (42.4 cM).

J:101473

Microarray gene chip technology was used to identify differentially expressed candidate genes for the arthritis QTL on mouse Chromosome 3 named Cia5. The Cia5 QTL microarray chip contains 163 genes found between 95.3 Mb and 109.7 Mb on mouse Chromosome 3. (This region spans markers D3Mit101 to D3Mit103.) Gene expression in lymph nodes, spleen, and paws was compared between the resistant Cia5 congenic and susceptible B10.RIII background strain. Animals were immunized with 100 ug of bovine CII at 12 weeks of age. Gene expression was evaluated at 0, 6, and 12 days after immunization. A total of 26 genes in the Cia5 locus were found to have significant expression differences (P<0.05) between the congenic and B10.RIII. These genes were found in 2 clusters corresponding to Cia21 and Cia22. Some notable candidate genes are described below.

Chi3l3 (50.5 cM; 105.9 Mb) is downregulated in congenic animals in spleen (all time points) and lymph nodes (day 6).

Vav3 (109.1 Mb) is upregulated in congenic animals in spleen (all time points), lymph nodes (day 0), and paws (days 6 and 12).

Gpr89 (96.3 Mb) is upregulated in congenic animals in spleen (all time points) and lymph nodes (day 0).

Ptpn22 (103.2 Mb) is downregulated in congenic animals in lymph nodes (day 0).

Cd53 (50.5 cM; 106.5 Mb) is upregulated in B10.RIII in spleen (day 12) and lymph nodes (day 0).

Gstm1 (107.8 Mb) is upregulated in B10.RIII in spleen and lymph nodes at day 0, but is downregulated after immunization.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:50472

173 (B10.RIII x RIIIS/J)F2 intercross animals were used to map novel loci associated with collagen-induced arthritis. Both strains share the H-2r MHC locus. B10.RIII is extremely susceptible to collagen-induced arthritis with 80-100% of the animals developing severe arthritis approximately 35 days after induction of disease. RIIIS/J is resistant and does not develop arthritis after induction. 55% of (B10.RIII x RIIIS/J)F1 animals develop arthritis after induction, and 45% of (B10.RIII x RIIIS/J)F2 animals develop arthritis after induction with wide variability in degree of disease severity. There appears to be a dominant, sex-influenced mode of disease inheritance. Male animals are more susceptible to arthritis than female animals. 121 markers covering 78% of the mouse genome at an average spacing of 20 cM were typed for QTL analysis.

Cia5 mapped to a region of chromosome 3 spanning 35.2 cM - 52.5 cM with a peak LOD score of 4.12 at D3Mit72 (39.7 cM). This locus was confirmed in an intercross using (B10.RIII x RIIIS/J)F2 x B10.RIII N4 backcross (N4I2) animals. B10.RIII-derived alleles contribute to recessively inherited disease susceptibility at this locus. Cia5 maps near loci for susceptibility to Theiler's murine encephalomyelitis virus (Tmevd2 at 46cM) and insulin dependent diabetes (Idd17 at 39 cM; Idd10 at 48. 5cM).

A suggestive QTL, Cia10, mapped to a region of chromosome 13 spanning 51 cM - 72 cM with a peak LOD score of 3.13 approximately 4 cM distal to D13Mit72 (51 cM). B10.RIII-derived alleles also contribute to recessively inherited disease susceptibility at this locus. Animals homozygous for B10.RIII alleles at Cia10 and Cia5 develop the most severe disease phenotype.

References

• Original: J:50472 Jirholt J, et al., Genetic linkage analysis of collagen-induced arthritis in the mouse. Eur J Immunol. 1998 Oct;28(10):3321-8
• All: 3 reference(s)