Experiment
A population of 290 (DBA/1J x FVB/N)F2 animals were reanalyzed with suggestive significant thresholds to identify additional QTL associated with susceptibility to collagen-induced arthritis. Parental strain DBA/1J displays susceptibility to CIA whereas parental strain FVB/N is resistant. Six suggestive loci were mapped on chromosome 6 (D6Mit328), chromosome 7 (D7Mit248), chromosome 10 (D10Mit261), chromosome 11 (D11Mit126), chromosome 18 (D18Mit222) and chromosome 19 (D19Mit90). An additional 308 (DBA/1Jx FVB/N)F11/12 advanced intercross line (AIL) animals were genotyped for 60 markers to confirm the suggestive QTL. The only locus to maintain statistical significance was at 51 cM (116.7 Mb) on chromosome 6 at D6Mit115 (p=0.00021). This locus coincides with previously identified QTL Cia3 (collagen induced arthritis 3) and has been named Cia43. FVB/N-derived alleles at Cia43 confer increased arthritis disease severity with an additive mode of inheritance. The Cia43 QTL interval was narrowed to a 5.6 Mb region between D6Mit329 (114.1Mb) and rs30265977 (119.7 Mb).
SNP analysis of DBA/1J and FVB/N strains across the Cia43 interval revealed 32 non synonymous SNPs in 14 genes. Expression profile analysis detected different levels of Timp4 (46 cM) and Cacna1c (56cM) mRNA in DBA/1J and FVB/N inbred strains. The Cia43 locus corresponds to Pia7 and Cia13 on rat Chromosome 4. Regions of human Chromosomes 3 and 12 display linkage to rheumatoid arthritis and are orthologous with mouse Cia43. Comparison of overlapping intervals between rat, mouse and human identified 29 genes common to all three species. Five of these genes contain nonsynonymous SNPs between DBA/1J and FVB/N sequences. These genes are Timp4 (46 cM), Tmem40, Mbd4 (50.3 cM), Cacna1c (56 cM) and Lrtm2.
Cia40(67 cM) on chromosome 11 and a locus at 41 cM on mouse Chromosome 19 near D19Mit90 also displayed suggestive linkage to CIA in both F2 and AIL populations. Authors suggest these loci may be small effect QTL.
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