Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis.
OBJECTIVE
Proteoglycan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA), both in terms of its pathology and its genetics. PGIA can only be induced in susceptible murine strains and their F2 progeny. As with RA, the genetics are complex, containing both major histocompatibility complex (MHC)-related and non-MHC-related components. Our goal was to identify the underlying non-MHC-related loci that confer PGIA susceptibility.


METHODS
We used 106 polymorphic markers to perform simple sequence-length polymorphism analysis on F2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2d haplotype, this cross permits identification and analysis of non-MHC-related genes.


RESULTS
We identified a total of 12 separate quantitative trait loci (QTL) associated with PGIA, which we have named Pgia1 through Pgia12. QTLs associated with the inflammatory symptoms of PGIA were linked to chromosomes 7, 9, 15 (2 separate loci), 16, and 19. QTLs associated with autoantibody production were identified on chromosomes 1, 2, 7, 8, 10, 11, 16, and 18. QTLs on chromosomes 7 and 16 showed linkage to both inflammation and autoantibody production, suggesting a shared regulatory component in arthritis induction. The first inflammation QTL on chromosome 15 and the autoantibody QTL on chromosome 7 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds.


CONCLUSIONS
These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.
Otto
J M
JM
Department of Biochemistry, Rush University at Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Cs-Szabó
G
G
Gallagher
J
J
Velins
S
S
Mikecz
K
K
Buzás
E I
EI
Enders
J T
JT
Li
Y
Y
Olsen
B R
BR
Glant
T T
TT
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000276:immunology*; D002885:Chromosomes, Human, Pair 16; D002897:Chromosomes, Human, Pair 7; D004195:Disease Models, Animal; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA
D001323:Autoantibodies