Evaluation of quantitative trait loci regulating severity of mycobacterial adjuvant-induced arthritis in monocongenic and polycongenic rats: identification of a new regulatory locus on rat chromosome 10 and evidence of overlap with rheumatoid arthritis susceptibility loci.
OBJECTIVE
To evaluate the regulatory potential of genetic loci controlling Mycobacterium butyricum adjuvant-induced arthritis (Mbt-AIA) using mono- and polycongenic rats.


METHODS
Of 4 quantitative trait loci (QTLs) that regulate Mbt-AIA, F344 alleles at 3 of these loci, Aia1, Aia2, and Aia3, are associated with lower arthritis severity, whereas F344 alleles at Aia4 are associated with greater arthritis severity. In this study, we constructed congenic lines by transferring 1 or more of the F344 genomic segments containing Aia1, Aia2, and Aia3 onto the DA genome. We comparatively evaluated their responses to Mbt-AIA with the responses of parental DA and F344 rats.


RESULTS
Aia1, encompassing the rat major histocompatibility complex, reduced arthritis severity in monocongenic rats of both sexes. The arthritis-lowering effects of Aia2 and Aia3 were sex-influenced and were therefore observed in only males and only females, respectively. Polycongenic rats containing F344 genomic regions at Aia1, Aia2, and Aia3 developed Mbt-AIA of relatively greater severity than did F344 rats, implying that in DA and F344 rats, there could be other Mbt-AIA loci in addition to Aia1, Aia2, Aia3, and Aia4. To test the possibility that some of these Mbt-AIA-regulatory loci may colocalize with other arthritis QTLs, we evaluated Mbt-AIA in DA.F344 monocongenic rats containing collagen-induced arthritis QTLs. Cia5 (the QTL region on chromosome 10), but not Cia5a, Cia4, or Cia6, also regulated Mbt-AIA, and was named Aia5.


CONCLUSIONS
F344 genomic regions at Aia1, Aia2, and Aia3 and the newly identified Aia5 contain genes that reduce Mbt-AIA severity in DA rats. These Mbt-AIA-regulatory loci overlap rheumatoid arthritis-susceptibility loci in humans.
Joe
Bina
B
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.
Cannon
Grant W
GW
Griffiths
Marie M
MM
Dobbins
David E
DE
Gulko
Pércio S
PS
Wilder
Ronald L
RL
Remmers
Elaine F
EF
D000483:Alleles; D000818:Animals; D020296:Animals, Congenic; D001169:Arthritis, Experimental / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009161:Mycobacterium; D019655:Quantitative Trait, Heritable; D051381:Rats; D011916:Rats, Inbred F344; D012720:Severity of Illness Index; D012737:Sex Factors; D013047:Specific Pathogen-Free Organisms