Cia6^DBA/1J
QTL Variant Detail

Summary

• QTL variant: Cia6^DBA/1J
• Name: collagen induced arthritis QTL 6; DBA/1J
• MGI ID: MGI:2156517
• QTL: Cia6 Location: Chr6:4464884-87403016 bp Genetic Position: Chr6, cM position of peak correlated region/allele: 32.53 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: DBA/1J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers arthritis resistance compared to C57BL/10SnSg. (J:57012)
• Inheritance: Recessive

Notes

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).

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

J:57012

To identify collagen-induced arthritis susceptibility loci outside of the MHC, crosses between the DBA/1 and the less susceptible B10.Q strain were analyzed. Analysis of 224 (B10.Q x DBA/1)F2 intercross mice identified a locus, D6Mit19, with a LOD score of 4.7 [chi square = 10.42 with 2df (p = 0.0055)] associated with the arthritis onset trait explaining ~16% of the genetic variance. Figure 2 displays QTL as mapping between D6Mit9 and D6Mit86.

The disease promoting allele was dominantly inherited from the B10.Q strain, because a delayed onset of disease was associated with the DBA/1 allele in a recessive manner.

Analysis of 86 [(B10.Q x DBA/1)F1 x B10.Q]F2 backcross mice confirmed the existence of the Cia6 QTL. Most significant association was with the D6Mit188 marker (Z = 2.7, chi square = 8.01, p = 0.0047).

F2 backcross mice heterozygous for relevant markers on Chromosome 6 were mated with B10.Q mice. Genotype analysis of 132 N3 backcross mice showed association of the onset trait with D6Mit124 (Z=2.5, p = 0.0092). Putative candidate genes in the region include the Igk gene family, Il12a, Il17r, Il5a and the Tcrb gene family.

J:201946

Collagen-induced arthritis (CIA) is the most commonly used model of rheumatoid arthritis (RA) in mice. In this study a known locus, Cia6, and a genomic region of Chromosome 14 were dissected using a partial advanced intercross (PAI) and a collection of congenic strains.

The congenics used for the PAI [[B10.D1-(D6Mit86-D6Mit188) H2^q/Rhd, B10.D1-(D6Mit268-D6Mit65) H2^q/Rhd and B10.D1-(D14Mit212-D14Mit160) H2^q/Rhd] were produced as speed congenics by marker assisted backcrossing of the susceptible DBA/1 (DQ) mice to the resistant, recipient strain C57BL/10.Q for seven generations. Four hundred and eighty four male, mice were tested in arthritis experiments. Seven markers were either linked to arthritis in single locus scans or involved in significant interactions detected in a two-locus scan.

To confirm and further define the indicated locus regions, subcongenic strains were produced by backcrossing selected DBA/1 fragments from the PAI to the B10.Q background. Two hundred and fifty six heterozygous, male mice and 273 heterozygous, female mice were tested for CIA susceptibility and antibody production. The peak markers and marker intervals found in the congenic mice correlated well with the loci found in the PAI. Three new loci were detected on Chromosome 6 and four new loci on Chromosome 14.

In the PAI, neighboring markers Cia6a (peak marker D6Mit307) and Cia6b (peak marker interval D6Mit268-D6Mit90) were both linked to protection from the disease. Linkage data suggests that the two markers are two distinct loci. Cia6a was linked to the onset of disease (LOD 4.6) and to total IgG production (LOD 3.3). Cia6b was linked to both onset (LOD 5.3) and incidence of disease (LOD 2.3) as well as IgG2a production (LOD 3.8). There was an epistatic interaction between the two loci affecting the onset of disease.

The congenic mice had significantly lower incidence (p=0.004), accumulated score (p=0.04), IgG1 (p=0.002), IgG2a (p=0.0002) and IgG3 (p=0.0001) in both males and females. However, the recombinations available were not sufficient to split the two loci.

J:201946

Collagen-induced arthritis (CIA) is the most commonly used model of rheumatoid arthritis (RA) in mice. In this study a known locus, Cia6, and a genomic region of Chromosome 14 were dissected using a partial advanced intercross (PAI) and a collection of congenic strains.

The congenics used for the PAI [[B10.D1-(D6Mit86-D6Mit188) H2^q/Rhd, B10.D1-(D6Mit268-D6Mit65) H2^q/Rhd and B10.D1-(D14Mit212-D14Mit160) H2^q/Rhd] were produced as speed congenics by marker assisted backcrossing of the susceptible DBA/1 (DQ) mice to the resistant, recipient strain C57BL/10.Q for seven generations. Four hundred and eighty four male, mice were tested in arthritis experiments. Seven markers were either linked to arthritis in single locus scans or involved in significant interactions detected in a two-locus scan.

To confirm and further define the indicated locus regions subcongenic strains were produced by backcrossing selected DBA/1 fragments from the PAI to the B10.Q background. Two hundred and fifty six heterozygous, male mice and 273 heterozygous, female mice were tested for CIA susceptibility and antibody production. The peak markers and marker intervals found in the congenic mice correlated well with the loci found in the PAI. Three new loci were detected on Chromosome 6 and four new loci on Chromosome 14.

In the PAI Cia6c, mapping to peak marker D6Mit74 on chromosome 6, was represented by a weak interaction with Cia6a that affected the severity of arthritis and an interaction with Cia49 affecting IgG1 production.

In congenic mice Cia6c, peak marker D6Mit74, increased IgG1 (p=0.003), IgG2a (p=0.007) and IgG3 (p=0.005) production in female mice but not in males. Disease susceptibility was not significantly affected in either sex. Figure 1 displays the QTL mapping between D6Mit207 and D6Mit17.

References

• Original: J:57012 Yang HT, et al., Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat. J Immunol. 1999 Sep 1;163(5):2916-21
• All: 1 reference(s)