Identification and isolation of dominant susceptibility loci for pristane-induced arthritis.
Rheumatoid arthritis is a chronic inflammatory autoimmune disorder, controlled by multiple genes as well as environmental factors. With animal models, like the pristane-induced arthritis (PIA) in rats, it is possible to reduce the environmental effects and the genetic heterogeneity to identify chromosomal regions harboring genes responsible for the arthritis development. The PIA model has proved to be useful for identifying gene regions controlling different phases of the disease based on intercrosses between the resistant E3 and the susceptible DA rat. We have now performed a high-powered backcross analysis that confirms previous intercross-based data but also identifies additional loci. Earlier identified PIA loci were reproduced with high significance; Pia1 (MHC region on chromosome 20), Pia4 (chromosome 12), and Pia7 (chromosome 4) are all major regulators of PIA severity and were also found to operate in concert. These three loci were verified in congenic strains using both disease- and arthritis-inflammatory-related subphenotypes as traits. We were also able to detect five new quantitative trait loci with dominant effects on PIA: Pia10, Pia12, Pia13, Pia14, and Pia15 on chromosomes 10, 6, 7, 8, and 18, respectively. These data highlight the usefulness of the statistical power obtained in a backcross of a complex disease like arthritis.
Olofsson
Peter
P
Section for Medical Inflammation Research, Lund University, Lund, Sweden.
Holmberg
Jens
J
Pettersson
Ulf
U
Holmdahl
Rikard
R
D000818:Animals; D020296:Animals, Congenic; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D002274:Carcinogens, Environmental / Q000633:toxicity; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D008126:Lod Score; D008297:Male; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D011919:Rats, Inbred Strains; D013729:Terpenes / Q000633:toxicity*
D002274:Carcinogens, Environmental; D005819:Genetic Markers; D013729:Terpenes; C009042:pristane