Human Molecular Genetics Advance Access originally published online on July 8, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 17 2087-2096
DOI: 10.1093/hmg/ddg224
© 2003 Oxford University Press
High resolution mapping of an arthritis susceptibility locus on rat chromosome 4, and characterization of regulated phenotypes
1Department of Medicine, Rheumatology Unit, Karolinska Institutet, S-171 76 Stockholm, Sweden, 2Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway and 3Department of Diabetes and Endocrinology, Lund University, S-205 02 Malmö, Sweden
Received March 3, 2003; Accepted July 2, 2003
The rat Natural Killer cell gene Complex (NKC) encodes molecules that can regulate immunity. It is located within an interval on DA rat chromosome 4 (RNO4) that is linked to immune-mediated inflammatory joint diseases, including oil-induced arthritis (OIA). We aimed to test the hypothesis that NKC regulates arthritis, by performing advanced mapping of arthritis and additional phenotypes induced by an intradermal injection of incomplete Freund's adjuvant-oil. Reciprocal transfer of RNO4 intervals established that alleles from DA confer arthritis susceptibility to inbred LEW.1AV1 and PVG.1AV1 rats, whereas LEW.1AV1 and PVG.1AV1 alleles confer resistance to inbred DA. Subcongenic strains with PVG.1AV1 alleles introduced on DA allowed mapping of disease predisposition to 0.8 cM on the cytogenetic band 4q42, within the quantitative trait locus oil-induced arthritis-2 (Oia2), but outside the NKC. Alleles in Oia2 regulated arthritis in an additive fashion, and determined arthritis incidence, severity and day of onset, in both males and females. Besides macroscopic joint-inflammation, Oia2 also regulated other oil-induced phenotypes, including lymphoplasia and plasma levels of the inflammation marker 
1-acid glycoprotein. The high-impact Oia2 region harbors gene sequences similar to human C3AR1, Ribosomal protein L7, DNAJA2, C-type lectins, C1s and CD163. These candidate disease genes may be of general interest, given that rat 4q42, and the syntenic mouse 6F2 and human 12p13 regions are linked to several inflammatory diseases, including rheumatoid arthritis.
* To whom correspondence should be addressed at: Rheumatology Unit, Center for Molecular Medicine, L8:04, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tel: +46 851775609; Fax: +46 851775562; Email: johnny.lorentzen{at}cmm.ki.se
The authors wish it to be known that, in their opinion, these authors contributed equally to this work.
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