Experiment
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).