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Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis
  1. C McKinney1,
  2. M E Merriman1,
  3. P T Chapman2,
  4. P J Gow3,
  5. A A Harrison4,
  6. J Highton5,
  7. P B B Jones6,
  8. L McLean7,
  9. J L O’Donnell2,
  10. V Pokorny7,
  11. M Spellerberg2,
  12. L K Stamp2,
  13. J Willis8,
  14. S Steer9,
  15. T R Merriman1
  1. 1
    Department of Biochemistry, University of Otago, Dunedin, New Zealand
  2. 2
    Department of Rheumatology, Christchurch Hospital, Christchurch, New Zealand
  3. 3
    Department of Rheumatology, Middlemore Hospital, Auckland, New Zealand
  4. 4
    Wellington Regional Rheumatology Unit, Hutt Hospital, Wellington, New Zealand
  5. 5
    Department of Medicine, University of Otago, Dunedin, New Zealand
  6. 6
    Queen Elizabeth Hospital, Rotorua, New Zealand
  7. 7
    Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
  8. 8
    Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand
  9. 9
    Kings College Hospital NHS Foundation Trust, London, UK
  1. T R Merriman, Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand; tony.merriman{at}


Objective: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by β-chemokines is a feature of autoimmunity, and that the CCR5Δ32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D).

Methods: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian.

Results: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08–1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75–1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98–2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00–1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Δ32).

Conclusions: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Δ32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

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  • Funding: This work was supported by the Health Research Council of New Zealand, the Arthritis Research Campaign in the UK, Arthritis New Zealand, the New Zealand Child Health Research Foundation and NHS Research and Development funding for recruitment undertaken at Guy’s and St. Thomas’ and Lewisham hospitals.

  • Competing interests: None declared.