Cia24^DBA/1J
QTL Variant Detail

Summary

• QTL variant: Cia24^DBA/1J
• Name: collagen induced arthritis QTL 24; DBA/1J
• MGI ID: MGI:5558878
• QTL: Cia24 Location: Chr2:24679115-33523172 bp Genetic Position: Chr2, Syntenic

Variant origin

• Strain of Specimen: DBA/1J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased collagen-induced arthritis severity compared to FVB/N (J:116665)

Notes

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

J:94347

Linkage analysis was performed on 290 animals from a (DBA/1J x FVB/N)F2 intercross to identify QTLs associated with arthritis traits. 126 polymorphic markers with 92% coverage of the mouse genome at an average spacing of 11.5 cM were used for the genome scan. Parental strain DBA/1J is susceptible to collagen-induced arthritis whereas parental strain FVB/N is resistant. Experimental animals were immunized with bovine collagen at 8-12 weeks of age to induce arthritis.

QTLs Cia24 and Cia25 were detected on mouse Chromosome 2. Both Cia24 and Cia25 showed linkage to D2Mit81 at 13.5 cM. Cia24 is associated with arthritis severity (LOD=12.1) and Cia25 is associated with onset of phenotype (LOD=10.6). The QTL interval is flanked by markers D2Mit81 and D2Mit367. A potential candidate gene for Cia24 and Cia25 is Hc at 23.5 cM. Parental strain FVB/N has a 2 bp deletion in the Hc exon 5 region, which results in Hc deficiency. The Hc deficiency phenotype cosegregates with decreased arthritis severity in (DBA/1J x FVB/N)F2 animals.

Novel QTL Trmq3 (T cell ratio modifier QTL 3) mapped to 65 cM on mouse Chromosome 2 near D2Mit398. This locus is linked to CD4:CD8 ratio (LOD=5). FVB/N-derived alleles at Trmq3 confer increased CD4:CD8 ratio. The QTL interval of Trmq3 isflanked by markers D2Mit61 and D2Mit395. Potential candidate genes for Trmq3 are Notch1 (15 cM) and Bcl2l1 (87.5 cM). Trmq3 maps near the previously identified QTL Trmq2 (52 cM).

Novel QTL Cia27 (collagen induced arthritis 27) mapped to 60 cM on mouse Chromosome 5 near D5Mit277. This locus is associated with collagen-specific IgG2a antibody levels (LOD=4.3). The QTL interval is flanked by markers D5Mit201 and D5Mit425. DBA/1J-derived alleles at Cia27 confer increasedIgG2a antibodies. Cia27 and Cia29 showevidence of interaction in affecting IgG2a levels (LOD=10.34).

Novel QTL Cia28 (collagen induced arthritis 28) mapped to 52 cM on mouse Chromosome 13 near D13Mit144. This locus is linked to collagen-specific IgG1 antibody levels (LOD=3.2). The QTL interval of Cia28 is flanked by markers D13Mit13 and D13Mit144. Cia28 shows evidence of interaction with Cia9 on mouse Chromosome 1 (D1Mit111) in affecting IgG1 levels (LOD=9.12).

Novel QTL Cia29 (collagen induced arthritis 29) mapped to 52 cM on mouse Chromosome 10 near D10Mit96. This locus is linked to collagen-specific IgG1 antibody levels (LOD=3.6). The QTL interval of Cia29 is flanked by markers D10Mit261 and D10Mit14. Previously identified arthritis QTL Cia8 (40.4 cM) maps near Cia29.

Novel QTL Lp1 (lymphocyte proliferation 1) mapped to 31 cM on mouse Chromosome 16 near D16Mit138. This locus is linked to lymphocyte proliferation (LOD=3.8). The QTL interval for Lp1 is flanked by markers D16Mit160 and D16Mit139. Lp1 maps nearpreviously identified QTL Eae11 (41 cM).

J:116665

Previously identified QTLs Cia24, Cia27, and Trmq3 were refined using 308 advanced intercross line (AIL) animals derived from DBA/1J and FVB/NJ. Parental strain DBA/1J is susceptible to collagen-induced arthritis where as parental strain FVB/NJ is resistant.

Cia24 (34 cM) and Trmq3 (65 cM) were fine-mapped using 31 informative markers on mouse Chromosome 2. Cia24 exhibited peak linkage to CIA severity at marker Hc (LOD=3.35). The Cia24 interval was narrowed to a 12 Mb interval using AIL analysis. DBA/1J-derived alleles at Cia24 confer increased CIA severity with additive inheritance. SNP haplotype analysis using CIA susceptible and resistant strains further refined the QTL to a 2 Mb interval between 33.3 Mb and 35.3 Mb. Stom (24 cM), Glo1 (35.1 Mb), andGgta1(25 cM) are genes located within this interval exhibiting differential expression between DBA/1J and FVB/NJ. *Note: Glo1 is reported on Chromosome 17 according to mapping data in the Mouse Genome Database* Cia24 also showed linkage to CIA susceptibility (LOD=1.93), CIA onset (LOD=2.32), and area under the curve (AUC) (LOD=3.1).

Trmq3 exhibited peak linkage to CD4:CD8 ratios at D2Mit394 (53.6 cM) with LOD=3.5. FVB/NJ-derived alleles at Trmq3 confer increased CD4:CD8 ratios with additive inheritance.The QTL interval was narrowed to a 12 Mb region of chromosome 2. Twelve genes in this interval exhibit differential expression between DBA/1J and FVB/NJ. They are Rasgrp1 (65 cM), Thbs1 (65 cM), Chac1 (formerly 1810008K03Rik), 1500003O03Rik, Ltk (67 cM),Mga,Ubr1 (67.4 cM), Sord (66 cM, formerly Sdh1), Pldn (67.6 cM), Sema6d, Slc27a2, and Hdc (71 cM). B2m (69 cM) is another potential candidate gene. Cia27 also showed association with CIA susceptibility (LOD=2.9), CIA onset (LOD=2.5), severity (LOD=2.3), andAUC(LOD=1.8)

Cia27 (60 cM) was fine-mapped using 28 informative markers on mouse Chromosome 5. Peak linkage to IgG2a antibody (Ab) production occurred at marker rs3653889 (LOD=3.5). DBA/1J-derived alleles at Cia27 confer increased IgG2a Ab production. The QTL interval was narrowed to a 4.1 Mb region. Three genes in this interval were found to exhibit differential expression between DBA/1J and FVB/NJ- Tpcn1, Oas1a (67 cM), and Ptpn11. Trmq3 also showed suggestive association with CIA severity (LOD=1.45),CIAonset (LOD=1.49), susceptibility (LOD=1.28), and AUC (LOD=1.84).

References

• Original: J:94347 Bauer K, et al., Identification of new quantitative trait loci in mice with collagen-induced arthritis. Arthritis Rheum. 2004 Nov;50(11):3721-8
• All: 2 reference(s)