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:

Association of two functional polymorphisms in the CCR5 gene with juvenile rheumatoid arthritis

Genes & Immunity volume 7, pages 468–475 (2006)Cite this article

Abstract

Juvenile rheumatoid arthritis (JRA) is mediated by Th1-immune responses. In children with JRA, synovial T cells express high levels of the Th1-chemokine receptor CC chemokine receptor 5 (CCR5), which has been implicated in susceptibility to rheumatoid arthritis. To test the hypothesis that genetic variation in CCR5 is associated with susceptibility to JRA, we analyzed patterns of variation in the 5′cis-regulatory region of CCR5 in 124 multiplex families from a JRA-affected sibpair registry. After sequencing the upstream region of CCR5, variants were tested for association with JRA by transmission disequilibrium testing. A single nucleotide polymorphism, C-1835T, was significantly undertransmitted to children with early-onset JRA (P<0.01). C-1835T was genotyped in 424 additional simplex and multiplex families. CCR5-1835T allele was undertransmitted in the cohort of all probands with JRA (P<0.02), as well as in those with early-onset (P<0.01) or pauciarticular JRA (P<0.05). Another variant, a 32-bp deletion in the open reading frame of CCR5 (CCR5-Δ32) was also tested in ∼700 simplex and multiplex families. CCR5-Δ32 was also significantly undertransmitted to probands with early-onset JRA (P<0.05). Both variants are in regions under natural selection, and result in functional consequences. Our results suggest these CCR5 variants are protective against early-onset JRA.

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

Similar content being viewed by others

References

  1. Cassidy JT, Levinson JE, Bass JC, Baum J, Brewer Jr EJ, Fink CW et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986; 29: 274–281.

    Article  CAS  PubMed  Google Scholar 

  2. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390–392.

    PubMed  Google Scholar 

  3. Prahalad S, Ryan MH, Shear ES, Thompson SD, Giannini EH, Glass DN . Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum 2000; 43: 2335–2338.

    Article  CAS  PubMed  Google Scholar 

  4. Rosen P, Thompson S, Glass D . Non-HLA gene polymorphisms in juvenile rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: 650–656.

    CAS  PubMed  Google Scholar 

  5. Wynne-Roberts CR, Anderson C . Light- and electron-microscopic studies of normal juvenile human synovium. Semin Arthritis Rheum 1978; 7: 279–286.

    Article  CAS  PubMed  Google Scholar 

  6. Wynne-Roberts CR, Anderson CH, Turano AM, Baron M . Light- and electron-microscopic findings of juvenile rheumatoid arthritis synovium: comparison with normal juvenile synovium. Semin Arthritis Rheum 1978; 7: 287–302.

    Article  CAS  PubMed  Google Scholar 

  7. Wedderburn LR, Robinson N, Patel A, Varsani H, Woo P . Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum 2000; 43: 765–774.

    Article  CAS  PubMed  Google Scholar 

  8. Wedderburn LR, Woo P . Type 1, type 2 immune responses in children: their relevance in juvenile arthritis. Springer Semin Immunopathol 1999; 21: 361–374.

    Article  CAS  PubMed  Google Scholar 

  9. Thompson SD, Luyrink LK, Graham TB, Tsoras M, Ryan M, Passo MH et al. Chemokine receptor CCR4 on CD4+ T cells in juvenile rheumatoid arthritis synovial fluid defines a subset of cells with increased IL-4:IFN-gamma mRNA ratios. J Immunol 2001; 166: 6899–6906.

    Article  CAS  PubMed  Google Scholar 

  10. Eberhard BA, Laxer RM, Andersson U, Silverman ED . Local synthesis of both macrophage and T cell cytokines by synovial fluid cells from children with juvenile rheumatoid arthritis. Clin Exp Immunol 1994; 96: 260–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Murray KJ, Grom AA, Thompson SD, Lieuwen D, Passo MH, Glass DN . Contrasting cytokine profiles in the synovium of different forms of juvenile rheumatoid arthritis and juvenile spondyloarthropathy: prominence of interleukin 4 in restricted disease. J Rheumatol 1998; 25: 1388–1398.

    CAS  PubMed  Google Scholar 

  12. Ozen S, Tucker LB, Miller LC . Identification of Th subsets in juvenile rheumatoid arthritis confirmed by intracellular cytokine staining. J Rheumatol 1998; 25: 1651–1653.

    CAS  PubMed  Google Scholar 

  13. Mack M, Bruhl H, Gruber R, Jaeger C, Cihak J, Eiter V et al. Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis. Arthritis Rheum 1999; 42: 981–988.

    Article  CAS  PubMed  Google Scholar 

  14. Pharoah DS, Varsani H, Tatham RW, Newton KR, de Jager W, Prakken BJ et al. Expression of the inflammatory chemokines CCL5, CCL3 and CXCL10 in juvenile idiopathic arthritis, and demonstration of CCL5 production by an atypical subset of CD8+ T cells. Arthritis Res Ther 2006; 8: R50.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN . Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett 1997; 57: 117–120.

    Article  CAS  PubMed  Google Scholar 

  16. Yang YF, Mukai T, Gao P, Yamaguchi N, Ono S, Iwaki H et al. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses. Eur J Immunol 2002; 32: 2124–2132.

    Article  CAS  PubMed  Google Scholar 

  17. Cooke SP, Forrest G, Venables PJ, Hajeer A . The delta32 deletion of CCR5 receptor in rheumatoid arthritis. Arthritis Rheum 1998; 41: 1135–1136.

    Article  CAS  PubMed  Google Scholar 

  18. Garred P, Madsen HO, Petersen J, Marquart H, Hansen TM, Freiesleben Sorensen S et al. CC chemokine receptor 5 polymorphism in rheumatoid arthritis. J Rheumatol 1998; 25: 1462–1465.

    CAS  PubMed  Google Scholar 

  19. Gomez-Reino JJ, Pablos JL, Carreira PE, Santiago B, Serrano L, Vicario JL et al. Association of rheumatoid arthritis with a functional chemokine receptor, CCR5. Arthritis Rheum 1999; 42: 989–992.

    Article  CAS  PubMed  Google Scholar 

  20. Pokorny V, McQueen F, Yeoman S, Merriman M, Merriman A, Harrison A et al. Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 487–490.

    Article  CAS  PubMed  Google Scholar 

  21. Prahalad S . Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun 2006; 7: 264–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS et al. A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci USA 2002; 99: 10539–10544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M et al. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 1998; 62: 1507–1515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  PubMed  Google Scholar 

  25. Cardon LR, Bell JI . Association study designs for complex diseases. Nat Rev Genet 2001; 2: 91–99.

    Article  CAS  PubMed  Google Scholar 

  26. Chen WM, Deng HW . A general and accurate approach for computing the statistical power of the transmission disequilibrium test for complex disease genes. Genet Epidemiol 2001; 21: 53–67.

    Article  CAS  PubMed  Google Scholar 

  27. Mummidi S, Bamshad M, Ahuja SS, Gonzalez E, Feuillet PM, Begum K et al. Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus. J Biol Chem 2000; 275: 18946–18961.

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez E, Bamshad M, Sato N, Mummidi S, Dhanda R, Catano G et al. Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. Proc Natl Acad Sci USA 1999: 12004–12009.

    Article  CAS  Google Scholar 

  29. Kostrikis LG, Huang Y, Moore JP, Wolinsky SM, Zhang L, Guo Y et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 1998; 4: 350–353.

    Article  CAS  PubMed  Google Scholar 

  30. Bamshad M, Wooding SP . Signatures of natural selection in the human genome. Nat Rev Genet 2003; 4: 99–111.

    Article  CAS  PubMed  Google Scholar 

  31. Galvani AP, Novembre J . The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Microbes Infect 2005; 7: 302–309.

    Article  CAS  PubMed  Google Scholar 

  32. Novembre J, Galvani AP, Slatkin M . The geographic spread of the CCR5 Delta32 HIV-resistance allele. PLoS Biol 2005; 3: e339.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sabeti PC, Walsh E, Schaffner SF, Varilly P, Fry B, Hutcheson HB et al. The case for selection at CCR5-Delta32. PLoS Biol 2005; 3: e378.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Moroldo MB, Tague BL, Shear ES, Glass DN, Giannini EH . Juvenile rheumatoid arthritis in affected sibpairs. Arthritis Rheum 1997; 40: 1962–1966.

    Article  CAS  PubMed  Google Scholar 

  35. Nickerson DA, Tobe VO, Taylor SL . PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 1997; 25: 2745–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  37. Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fink CW, Fernandez-Vina M, Stastny P . Clinical and genetic evidence that juvenile arthritis is not a single disease. Pediatr Clin North Am 1995; 42: 1155–1169.

    Article  CAS  PubMed  Google Scholar 

  39. Prahalad S, Glass DN . Is juvenile rheumatoid arthritis/juvenile idiopathic arthritis different from rheumatoid arthritis? Arthritis Res 2002; 4: 303–310.

    Article  PubMed Central  Google Scholar 

  40. Murray KJ, Moroldo MB, Donnelly P, Prahalad S, Passo MH, Giannini EH et al. Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arthritis Rheum 1999; 42: 1843–1853.

    Article  CAS  PubMed  Google Scholar 

  41. Prahalad S . Subtype-specific outcomes in juvenile idiopathic arthritis: a systematic review. Curr Med Literature: Rheumatol 2006; 25: 1–9.

    Article  Google Scholar 

  42. Thompson SD, Moroldo MB, Guyer L, Ryan M, Tombragel EM, Shear ES et al. A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage. Arthritis Rheum 2004; 50: 2920–2930.

    Article  CAS  PubMed  Google Scholar 

  43. Ackerman H, Usen S, Jallow M, Sisay-Joof F, Pinder M, Kwiatkowski DP . A comparison of case-control and family-based association methods: the example of sickle-cell and malaria. Ann Hum Genet 2005; 69: 559–565.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR-50177, N01-AR-42272, P01-AR-048929, P30-AR-47363), National Center for Research Resources (M01-RR-00064); The Cincinnati Pediatric Rheumatology Tissue Repository, and The Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; The Val A Browning Charitable Foundation, The Primary Children's Medical Center Foundation, The Clinical Genetics Research Program, and The Children's Health Research Center Salt Lake City, UT, USA. We also thank the families that participated in this project.

Author information

Authors and Affiliations

  1. Division of Immunology and Rheumatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    S Prahalad, J F Bohnsack, A Whiting & B Clifford

  2. Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT, USA

    L B Jorde, D Dunn & R Weiss

  3. William S. Rowe Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    M Moroldo, S D Thompson & D N Glass

  4. Department of Pediatrics and Genome Sciences, University of Washington, Seattle, WA, USA

    M J Bamshad

Authors
  1. S Prahalad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J F Bohnsack
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L B Jorde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Whiting
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Clifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Dunn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Moroldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S D Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D N Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M J Bamshad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Prahalad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prahalad, S., Bohnsack, J., Jorde, L. et al. Association of two functional polymorphisms in the CCR5 gene with juvenile rheumatoid arthritis. Genes Immun 7, 468–475 (2006). https://doi.org/10.1038/sj.gene.6364317

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364317

Keywords

This article is cited by

Search

Advanced search

Quick links