Experiment
Linkage analysis was performed on a population of (BALB/c x DBA/2)F2 intercross animals to identify loci associated with susceptibility to proteoglycan-induced ankylosing spondylitis. Animals were immunized with 100 ug of proteglycan at 12 weeks of age. Parental strain BALB/c is susceptible, exhibiting 61.5% incidence of ankylosing spondylitis after proteoglycan inoculation, whereas parental strain DBA/2 is resistant (4% incidence). 224 polymorphic markers at an average spacing of 6.2 cM were used for the genome scan.
Significant linkage to spondylitis mapped to telomeric mouse Chromosome 18 with LRS=31. This locus, Pgis1 (proteoglycan induced spondylitis 1), was confirmed by composite interval mapping. The Pgis1 interval spans 54 Mb to 81 Mb and is flanked by markers D18Mit55 (25 cM) and D18Mit80 (50 cM). Homozygosity for DBA/2-derived alleles at Pgis1 confer increased spondylitis incidence and severity with a recessive mode of inheritance. Potential candidate genes mapping near the Pgis1 interval include Adamts19, Il17b, Cd74 (32 cM), Csf1r (30 cM), and Nfatc1 (54 cM). Previously identified autoimmune QTL near Pgis1 are Lbw6 (47 cM), Pgia11 (50 cM), Cia8 (40.4 cM), Eae25 (54 cM), and Heal9 (44 cM). Pgis1 is orthologous to regions on human Chromosomes 5q and 18q, which contain loci linked to human ankyolsing spondylitis.
Significant linkage to spondylitis mapped to mouse Chromsome 2 with LRS=16.9. This locus is named Pgis2 (proteoglycan induced spondylitis 2) and was confirmed by composite interval mapping near D2Mit241 (47.5 cM). The Pgis2 interval spans 26.4 Mb to 57 Mb and is flanked by markers D2Mit293 (11 cM) and D2Mit156 (32 cM). BALB/c-derived alleles at Pgis2 confer spondylitis susceptibility with a dominant mode of inheritance. Pgis2 also shows linkageto late onset spondylitis. Potential candidate genes near the Pgis2 interval include C8g (12.3 cM), the Il1 gene cluster, and Il1rn (10 cM). Previously identified autoimmune QTL mapping near Pgis2 are Abhr1 (10 cM), Abhr2 (30 cM), Cia2 (34 cM), Cia4 (34 cM), Stia2 (23.5 cM), and Eae21 (37 cM). Bone QTL Fcsa5 (14 cM) and Pcfm1 (15.3 cM) also map near Pgia2. Pgis2 is orthologous to regions on human Chromosomes 2q and 9, which contain loci for human ankylosing spondylitis.
Pgis1 and Pgis2 account for 40% of the phenotypic variance and these loci appear to interact. Penetrance of spondylitis susceptibility at Pgis1 depends on the presence of at least one BALB/c-derived allele at Pgis2. Therefore, F2 animals homozygous for DBA/2-derived alleles at Pgis1 and homozygous for BALB/c-derived alleles at Pgis2 exhibit the highest spondylitis incidence and severity.
Suggestive linkage to spondylitis susceptibility mapped to mouse Chromosomes 11, 12, 15, and 19. Suggestive linkage to serum IgG2a concentration mapped to 2 loci on mouse Chromosome 11 and to mouse Chromosomes 1 and5. Suggestive linkage to serum Il6 concentration mapped to central mouse Chromosome 14.
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