Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis.
OBJECTIVE
Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats.


METHODS
Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay.


RESULTS
DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA x BN)F1 rats (7 of 60) and 31% of (DA x BN)F2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA x BN)F2 rats.


CONCLUSIONS
Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.
Griffiths
M M
MM
Department of Veterans Affairs Medical Center, and University of Utah, Salt Lake City, USA.
Wang
J
J
Joe
B
B
Dracheva
S
S
Kawahito
Y
Y
Shepard
J S
JS
Reese
V R
VR
McCall-Vining
S
S
Hashiramoto
A
A
Cannon
G W
GW
Remmers
E F
EF
Wilder
R L
RL
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D001323:Autoantibodies / Q000032:analysis / Q000096:biosynthesis*; D002874:Chromosome Mapping; D003094:Collagen / Q000276:immunology*; D005260:Female; D005838:Genotype; D006824:Hybridization, Genetic; D007074:Immunoglobulin G / Q000096:biosynthesis; D008297:Male; D019655:Quantitative Trait, Heritable; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001323:Autoantibodies; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen