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.

  • Short Communication
  • Published:

Association analysis of the CCL3L1 copy number locus by paralogue ratio test in Norwegian rheumatoid arthritis patients and healthy controls

Genes & Immunity volume 13, pages 579–582 (2012)Cite this article

Subjects

Abstract

Genotyping of multiallelic copy number variants (CNVs) is technically difficult and can lead to inaccurate conclusions. This is reflected by inconsistent results published for the CNV C-C chemokine ligand 3-like 1 (CCL3L1) and its contribution to rheumatoid arthritis (RA) susceptibility. In order to draw robust conclusions about CCL3L1 involvement in RA, we have performed association analysis (CNVtools) using genotyping by the paralogue ratio test of a Norwegian RA case–control material (N=1877). We also analyzed the associations after stratification for anti-citrullinated peptide antibody (ACPA) status. Clear clusters representing specific copy number classes were evident, but significant differential bias was observed resulting in a systematic trend toward slightly higher apparent copy number for cases relative to controls. Controlling for bias revealed no significant differences in copy number distribution either between all patients and controls, or after ACPA stratification. Our results do not support involvement of the CCL3L1 CNV in RA susceptibility.

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

Similar content being viewed by others

References

  1. 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  Google Scholar 

  2. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357: 977–986.

    Article  CAS  Google Scholar 

  3. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  Google Scholar 

  4. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 2007; 357: 1199–1209.

    Article  CAS  Google Scholar 

  5. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 2010; 42: 508–514.

    Article  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008; 40: 1216–1223.

    Article  CAS  Google Scholar 

  8. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD et al. Global variation in copy number in the human genome. Nature 2006; 444: 444–454.

    Article  CAS  Google Scholar 

  9. Estivill X, Armengol L . Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies. PLoS Genet 2007; 3: 1787–1799.

    Article  CAS  Google Scholar 

  10. McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 2008; 40: 1166–1174.

    Article  CAS  Google Scholar 

  11. Perry GH, Ben-Dor A, Tsalenko A, Sampas N, Rodriguez-Revenga L, Tran CW et al. The fine-scale and complex architecture of human copy-number variation. Am J Hum Genet 2008; 82: 685–695.

    Article  CAS  Google Scholar 

  12. Pang AW, MacDonald JR, Pinto D, Wei J, Rafiq MA, Conrad DF et al. Towards a comprehensive structural variation map of an individual human genome. Genome Biol 2010; 11: R52.

    Article  Google Scholar 

  13. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315: 848–853.

    Article  CAS  Google Scholar 

  14. Willcocks LC, Lyons PA, Clatworthy MR, Robinson JI, Yang W, Newland SA et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008; 205: 1573–1582.

    Article  CAS  Google Scholar 

  15. Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S et al. Genome-wide association study of CNVs in 16 000 cases of eight common diseases and 3,000 shared controls. Nature 2010; 464: 713–720.

    Article  CAS  Google Scholar 

  16. Suzuki N, Nakajima A, Yoshino S, Matsushima K, Yagita H, Okumura K . Selective accumulation of CCR5+ T lymphocytes into inflamed joints of rheumatoid arthritis. Int Immunol 1999; 11: 553–559.

    Article  CAS  Google Scholar 

  17. Vierboom MP, Zavodny PJ, Chou CC, Tagat JR, Pugliese-Sivo C, Strizki J et al. Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5. Arthritis Rheum 2005; 52: 627–636.

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. 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  Google Scholar 

  20. Lindner E, Nordang GB, Melum E, Flato B, Selvaag AM, Thorsby E et al. Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis. BMC Med Genet 2007; 8: 33.

    Article  Google Scholar 

  21. Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L . Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol 2008; 26: 651–675.

    Article  CAS  Google Scholar 

  22. van OM, Bajema I, Levarht EW, Toes RE, Huizinga TW, van Laar JM . Differences in synovial tissue infiltrates between anti-cyclic citrullinated peptide-positive rheumatoid arthritis and anti-cyclic citrullinated peptide-negative rheumatoid arthritis. Arthritis Rheum 2008; 58: 53–60.

    Article  Google Scholar 

  23. Padyukov L, Seielstad M, Ong RT, Ding B, Ronnelid J, Seddighzadeh M et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis 2011; 70: 259–265.

    Article  Google Scholar 

  24. McKinney C, Merriman ME, Chapman PT, Gow PJ, Harrison AA, Highton J et al. Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Ann Rheum Dis 2008; 67: 409–413.

    Article  CAS  Google Scholar 

  25. Carpenter D, Walker S, Prescott N, Schalkwijk J, Armour JA . Accuracy and differential bias in copy number measurement of CCL3L1 in association studies with three auto-immune disorders. BMC Genomics 2011; 12: 418.

    Article  CAS  Google Scholar 

  26. Mamtani M, Rovin B, Brey R, Camargo JF, Kulkarni H, Herrera M et al. CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus. Ann Rheum Dis 2008; 67: 1076–1083.

    Article  CAS  Google Scholar 

  27. Field SF, Howson JM, Maier LM, Walker S, Walker NM, Smyth DJ et al. Experimental aspects of copy number variant assays at CCL3L1. Nat Med 2009; 15: 1115–1117.

    Article  CAS  Google Scholar 

  28. Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 2005; 37: 1243–1246.

    Article  CAS  Google Scholar 

  29. He W, Kulkarni H, Castiblanco J, Shimizu C, Aluyen U, Maldonado R et al. Reply to: ‘Experimental aspects of copy number variant assays at CCL3L1’. Nat Med 2009; 15: 1117–1120.

    Article  CAS  Google Scholar 

  30. Walker S, Janyakhantikul S, Armour JA . Multiplex Paralogue Ratio Tests for accurate measurement of multiallelic CNVs. Genomics 2009; 93: 98–103.

    Article  CAS  Google Scholar 

  31. Barnes C, Plagnol V, Fitzgerald T, Redon R, Marchini J, Clayton D et al. A robust statistical method for case-control association testing with copy number variation. Nat Genet 2008; 40: 1245–1252.

    Article  CAS  Google Scholar 

  32. Aldhous MC, Abu BS, Prescott NJ, Palla R, Soo K, Mansfield JC et al. Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn’s disease. Hum Mol Genet 2010; 19: 4930–4938.

    Article  CAS  Google Scholar 

  33. Fode P, Jespersgaard C, Hardwick RJ, Bogle H, Theisen M, Dodoo D et al. Determination of beta-defensin genomic copy number in different populations: a comparison of three methods. PLoS One 2011; 6: e16768.

    Article  CAS  Google Scholar 

  34. Shrestha S, Tang J, Kaslow RA . Gene copy number: learning to count past two. Nat Med 2009; 15: 1127–1129.

    Article  CAS  Google Scholar 

  35. Urban TJ, Weintrob AC, Fellay J, Colombo S, Shianna KV, Gumbs C et al. CCL3L1 and HIV/AIDS susceptibility. Nat Med 2009; 15: 1110–1112.

    Article  CAS  Google Scholar 

  36. Bhattacharya T, Stanton J, Kim EY, Kunstman KJ, Phair JP, Jacobson LP et al. CCL3L1 and HIV/AIDS susceptibility. Nat Med 2009; 15: 1112–1115.

    Article  CAS  Google Scholar 

  37. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Norwegian Bone Marrow Registry for making the control material available and Dr Stephen J Williams at the Fox Chase Cancer center, Philadelphia, USA for providing the OVCAR-5 reference sample. This work was supported by the Norwegian Research Council and Oslo University Hospital, by the South-Eastern Norway Regional Health Authority and by a Wellcome Trust grant awarded to JALA (number 083929).

Author information

Author notes

  1. G B N Nordang and D Carpenter: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway

    G B N Nordang, M K Viken & B A Lie

  2. School of Biology, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

    D Carpenter & J A L Armour

  3. Department of Immunology, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway

    M K Viken & B A Lie

  4. Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway

    T K Kvien

Authors
  1. G B N Nordang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Carpenter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M K Viken
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T K Kvien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J A L Armour
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B A Lie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G B N Nordang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nordang, G., Carpenter, D., Viken, M. et al. Association analysis of the CCL3L1 copy number locus by paralogue ratio test in Norwegian rheumatoid arthritis patients and healthy controls. Genes Immun 13, 579–582 (2012). https://doi.org/10.1038/gene.2012.30

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.30

Keywords

This article is cited by

Search

Advanced search

Quick links