Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22–q25 locus

Genes & Immunity volume 7, pages 335–341 (2006)Cite this article

Abstract

Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA × ACI) F2. As an initial step towards the positional cloning of the Cia27 gene, a 17 cM (21 Mb) interval from the DA strain (arthritis-susceptible) containing the two-logarithm of odds support interval comprising Cia27 was introgressed into the ACI (arthritis-resistant) background through genotype-guided congenic breeding. ACI.DA(Cia27) congenics developed a significantly more severe form of arthritis (CIA), with a 5.9-fold increase in median arthritis severity index, a parameter known to correlate with synovial inflammation, and cartilage and bone erosions, compared with ACI (P⩽0.001). The arthritis severity enhancing effect could be detected from day 21 onwards. Rats heterozygous at the congenic interval developed a disease similar to ACI rats, suggesting that DA alleles operate in a recessive manner. Levels of autoantibodies anti-rat type II collagen did not correlate with arthritis severity. Synovial tissue mRNA levels of interleukin-1β (IL-1β) were significantly increased in ACI.DA(Cia27) congenics compared with ACI. These results demonstrate that Cia27 harbors a novel arthritis severity regulatory gene. The identification of this gene should facilitate the identification of the rheumatoid arthritis gene mapped to the human syntenic region on chromosome 17q22–q25.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Seldin MF, Amos CI, Ward R, Gregersen PK . The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum 1999; 42: 1071–1079.

    Article  CAS  PubMed  Google Scholar 

  2. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43: 30–37.

    Article  CAS  PubMed  Google Scholar 

  3. Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R et al. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum 2003; 48: 906–916.

    Article  CAS  PubMed  Google Scholar 

  4. Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Monteiro J et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001; 68: 927–936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cornelis F, Faure S, Martinez M, Prud'homme JF, Fritz P, Dib C et al. New susceptibility locus for rheumatoid arthritis suggested by a genomewide linkage study. Proc Natl Acad Sci USA 1998; 95: 10746–10750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shiozawa S, Hayashi S, Tsukamoto Y, Goko H, Kawasaki H, Wada T et al. Identification of the gene loci that predispose to rheumatoid arthritis. Int Immunol 1998; 10: 1891–1895.

    Article  CAS  PubMed  Google Scholar 

  7. MacKay K, Eyre S, Myerscough A, Milicic A, Barton A, Laval S et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum 2002; 46: 632–639.

    Article  CAS  PubMed  Google Scholar 

  8. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003; 34: 395–402.

    Article  CAS  PubMed  Google Scholar 

  9. Okamoto K, Makino S, Yoshikawa Y, Takaki A, Nagatsuka Y, Ota M et al. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet 2003; 72: 303–312.

    Article  CAS  PubMed  Google Scholar 

  10. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75: 330–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lander E, Schork N . Genetic dissection of complex traits. Science 1994; 265: 2037–2048.

    Article  CAS  PubMed  Google Scholar 

  12. Joe B, Cannon GW, Griffiths MM, Dobbins DE, Gulko PS, Wilder RL et al. 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. Arthritis Rheum 2002; 46: 1075–1085.

    Article  CAS  PubMed  Google Scholar 

  13. Joe B, Remmers EF, Dobbins DE, Salstrom JL, Furuya T, Dracheva S et al. Genetic dissection of collagen-induced arthritis in chromosome 10 quantitative trait locus speed congenic rats: evidence for more than one regulatory locus and sex influences. Immunogenetics 2000; 51: 930–944.

    Article  CAS  PubMed  Google Scholar 

  14. Remmers EF, Joe B, Griffiths MM, Dobbins DE, Dracheva SV, Hashiramoto A et al. Modulation of multiple experimental arthritis models by collagen-induced arthritis quantitative trait loci isolated in congenic rat lines: different effects of non-major histocompatibility complex quantitative trait loci in males and females. Arthritis Rheum 2002; 46: 2225–2234.

    Article  CAS  PubMed  Google Scholar 

  15. Adarichev VA, Nesterovitch AB, Bardos T, Biesczat D, Chandrasekaran R, Vermes C et al. Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis. Arthritis Rheum 2003; 48: 1708–1720.

    Article  PubMed  Google Scholar 

  16. Meng H, Griffiths M, Remmers E, Kawahito Y, Li W, Neisa R et al. Identification of two novel female-specific non-MHC loci regulating collagen-induced arthritis severity and chronicity, and evidence of epistasis. Arthritis Rheum 2004; 50: 2695–2705.

    Article  CAS  PubMed  Google Scholar 

  17. Yamada R, Tanaka T, Unoki M, Nagai T, Sawada T, Ohnishi Y et al. Association between a single-nucleotide polymorphism in the promoter of the human interleukin-3 gene and rheumatoid arthritis in Japanese patients, and maximum-likelihood estimation of combinatorial effect that two genetic loci have on susceptibility to the disease. Am J Hum Genet 2001; 68: 674–685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jacob HJ . Functional genomics and rat models. Genome Res 1999; 9: 1013–1016.

    Article  CAS  PubMed  Google Scholar 

  19. Gulko PS, Kawahito Y, Remmers EF, Reese VR, Wang J, Dracheva SV et al. Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen- induced arthritis in rats. Arthrititis Rheum 1998; 41: 2122–2131.

    Article  CAS  Google Scholar 

  20. Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison WE, McFarland HF et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci USA 1998; 95: 9979–9984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wilder R, Remmers E, Kawahito Y, Gulko P, Cannon G, Griffiths M . Genetic factors regulating experimental arthritis in mice and rats. In: Theophilopoulos A (ed). Current Directions in Autoimmunity. Karger: Basel, 1999, pp 121–165.

    Google Scholar 

  22. Remmers EF, Longman RE, Du Y, O'Hare A, Cannon GW, Griffiths MM et al. A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats. Nat Genet 1996; 14: 82–85.

    Article  CAS  PubMed  Google Scholar 

  23. Brenner M, Meng HC, Yarlett NC, Joe B, Griffiths MM, Remmers EF et al. The non-MHC quantitative trait locus Cia5 contains three major arthritis genes that differentially regulate disease severity, pannus formation, and joint damage in collagen- and pristane-induced arthritis. J Immunol 2005; 174: 7894–7903.

    Article  CAS  PubMed  Google Scholar 

  24. Holm BC, Wei Xu H, Jacobsson L, Larsson A, Luthman H, Lorentzen JC . Rats made congenic for Oia3 on chromosome 10 become susceptible to squalene-induced arthritis. Hum Mol Genet 2001; 10: 565–572.

    Article  CAS  PubMed  Google Scholar 

  25. Barton A, Eyre S, Myerscough A, Brintnell B, Ward D, Ollier WE et al. High resolution linkage and association mapping identifies a novel rheumatoid arthritis susceptibility locus homologous to one linked to two rat models of inflammatory arthritis. Hum Mol Genet 2001; 10: 1901–1906.

    Article  CAS  PubMed  Google Scholar 

  26. Wilder RL, Remmers EF, Gulko PS, Joe B, Kawahito Y, Du Y et al. National Institutes of Arthritis and Musculoskeletal and Skin Diseases, Arthritis and Rheumatism Branch, Rat Genetic Database. http://www.niams.nih.gov/rtbc//ratgbase/index.htm 2000.

  27. Pasko D . Rat Genome Database Web Site., 2003.

  28. Griffiths MM, Cannon GW, Leonard PA, Reese VR . Induction of autoimmune arthritis in rats by immunization with homologous rat type II collagen is restricted to the RT1av1 haplotype. Arthritis Rheum 1993; 36: 254–258.

    Article  CAS  PubMed  Google Scholar 

  29. Kawahito Y, Cannon G, Gulko P, Remmers E, Longman R, Reese V et al. Localization of quantitative trait loci regulating adjuvant induced arthritis in rats: evidence for genetic factors common to multiple autoimmune diseases. J Immunol 1998; 161: 4411–4419.

    CAS  PubMed  Google Scholar 

  30. Brenner M, Braun C, Oster M, Gulko PS . Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity. Ann Rheum Dis 2006; 65 (3): 306–311.

    Article  CAS  PubMed  Google Scholar 

  31. Brenner M, Meng H, Yarlett N, Griffiths M, Remmers E, Wilder R et al. The non-MHC quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation and joint damage. Arthritis Rheum 2005; 52: 322–332.

    Article  CAS  PubMed  Google Scholar 

  32. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  33. ABI. User Bulletin #2 ABI 7700 Sequence Detection System. Applied Biosystems Inc.: Foster City, CA, 2001.

  34. Vingsbo-Lundberg C, Nordquist N, Olofsson P, Sundvall M, Saxne T, Pettersson U et al. Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats. Nat Genet 1998; 20: 401–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wester L, Olofsson P, Ibrahim SM, Holmdahl R . Chronicity of pristane-induced arthritis in rats is controlled by genes on chromosome 14. J Autoimmun 2003; 21: 305–313.

    Article  CAS  PubMed  Google Scholar 

  36. Dracheva SV, Remmers EF, Gulko PS, Kawahito Y, Longman RE, Reese VR et al. Identification of a new quantitative trait locus on Chromosome 7 controlling disease severity of collagen-induced arthritis in rats. Immunogenetics 1999; 49: 787–791.

    Article  CAS  PubMed  Google Scholar 

  37. Wernhoff P, Olofsson P, Holmdahl R . The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis. Arthritis Rheum 2003; 48: 3584–3596.

    Article  CAS  PubMed  Google Scholar 

  38. Olofsson P, Wernhoff P, Holmberg J, Holmdahl R . Two-loci interaction confirms arthritis-regulating quantitative trait locus on rat chromosome 6. Genomics 2003; 82: 652–659.

    Article  CAS  PubMed  Google Scholar 

  39. Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R . Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet 2003; 33: 25–32.

    Article  CAS  PubMed  Google Scholar 

  40. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

    Article  CAS  PubMed  Google Scholar 

  41. Sokka T, Willoughby J, Yazici Y, Pincus T . Databases of patients with early rheumatoid arthritis in the USA. Clin Exp Rheumatol 2003; 21: S146–S153.

    CAS  PubMed  Google Scholar 

  42. Zhou F, He X, Iwakura Y, Horai R, Stuart JM . Arthritis in mice that are deficient in interleukin-1 receptor antagonist is dependent on genetic background. Arthritis Rheum 2005; 52: 3731–3738.

    Article  CAS  PubMed  Google Scholar 

  43. Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196–2204.

    Article  CAS  PubMed  Google Scholar 

  44. Rioja I, Bush KA, Buckton JB, Dickson MC, Life PF . Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment. Clin Exp Immunol 2004; 137: 65–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Olofsson P, Holmberg J, Pettersson U, Holmdahl R . Identification and isolation of dominant susceptibility loci for pristane-induced arthritis. J Immunol 2003; 171: 407–416.

    Article  CAS  PubMed  Google Scholar 

  46. Furuya T, Salstrom JL, McCall-Vining S, Cannon GW, Joe B, Remmers EF et al. Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci. Hum Mol Genet 2000; 9: 2241–2250.

    Article  CAS  PubMed  Google Scholar 

  47. Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JR, Hearne CM et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 1991; 351: 542–547.

    Article  CAS  PubMed  Google Scholar 

  48. Butterfield RJ, Blankenhorn EP, Roper RJ, Zachary JF, Doerge RW, Teuscher C . Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am J Pathol 2000; 157: 637–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jackson AU, Galecki AT, Burke DT, Miller RA . Genetic polymorphisms in mouse genes regulating age-sensitive and age-stable T cell subsets. Genes Immun 2003; 4: 30–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang Y, Lefort J, Kearsey V, Lapa e Silva JR, Cookson WO, Vargaftig BB . A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma. Hum Mol Genet 1999; 8: 601–605.

    Article  CAS  PubMed  Google Scholar 

  51. Tomfohrde J, Silverman A, Barnes R, Fernandez-Vina MA, Young M, Lory D et al. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 1994; 264: 1141–1145.

    Article  CAS  PubMed  Google Scholar 

  52. Nair RP, Henseler T, Jenisch S, Stuart P, Bichakjian CK, Lenk W et al. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum Mol Genet 1997; 6: 1349–1356.

    Article  CAS  PubMed  Google Scholar 

  53. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996; 13: 464–468.

    Article  CAS  PubMed  Google Scholar 

  54. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506–511.

    Article  CAS  PubMed  Google Scholar 

  55. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36: 337–338.

    Article  CAS  PubMed  Google Scholar 

  56. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with Human SLE. Am J Hum Genet 2004; 75: 504–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by grant numbers R01-AR46213, R01-AR052439 and R01-AI54348, from NIAMS and NIAID (National Institutes of Health, NIH) to Dr P Gulko.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Rheumatology, The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY, USA

    M Brenner, T Laragione, N C Yarlett, W Li, A Mello & P S Gulko

Authors
  1. M Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Laragione
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N C Yarlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Mello
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P S Gulko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P S Gulko.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brenner, M., Laragione, T., Yarlett, N. et al. Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22–q25 locus. Genes Immun 7, 335–341 (2006). https://doi.org/10.1038/sj.gene.6364304

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364304

Keywords

This article is cited by

Search

Advanced search

Quick links