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Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.
  1. Cushla McKinney (cushla.mckinney{at}stonebow.otago.ac.nz)
  1. University of Otago, New Zealand
    1. Marilyn E Merriman (marilyn.merriman{at}stonebow.otago.ac.nz)
    1. University of Otago, New Zealand
      1. Peter T Chapman (peter.chapman{at}cdhb.govt.nz)
      1. Christchurch Hospital, New Zealand
        1. Peter J Gow (pgow{at}middlemore.co.nz)
        1. Middlemore Hospital, New Zealand
          1. Andrew A Harrison (andrew.harrison{at}stonebow.otago.ac.nz)
          1. University of Otago, New Zealand
            1. John Highton (john.highton{at}stonebow.otago.ac.nz)
            1. University of Otago, New Zealand
              1. Peter BB Jones
              1. QE Hospital, New Zealand
                1. Lachy McLean (mclean.lachy{at}gene.com)
                1. University of Auckland, New Zealand
                  1. John L O'Donnell (john.odonnell{at}cdhb.govt.nz)
                  1. Christchurch Hospital, New Zealand
                    1. Violetta Pokorny (mednov1{at}hotmail.com)
                    1. University of Auckland, New Zealand
                      1. Myfanwy Spellerberg (myfanwy.spellerberg{at}cdhb.govt.nz)
                      1. University of Auckland, New Zealand
                        1. Lisa Stamp (lisa.stamp{at}cdhb.govt.nz)
                        1. Christchurch Hospital, New Zealand
                          1. Jinny Willis (jinny.willis{at}cdhb.govt.nz)
                          1. Christchurch Hospital, New Zealand
                            1. Sophia Steer (sophia.2.steer{at}kcl.ac.uk)
                            1. Kings College Hospital, Denmark Hill, United Kingdom
                              1. Tony Merriman (tony.merriman{at}stonebow.otago.ac.nz)
                              1. University of Otago, New Zealand

                                Abstract

                                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 CCR5∆32 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 United Kingdom (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 (OR=1.34 [95% CI 1.08-1.66], P=0.009) but not the smaller UK RA cohort (OR=1.09 [0.75-1.60] P=0.643). There was evidence for association in the T1D cohort (OR=1.46 [0.98-2.20], P=0.064) and in the combined RA/T1D cohort (OR=1.30 [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 (CCR5∆32).

                                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; CCR5∆32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

                                • CCL3L1
                                • association
                                • copy number
                                • polymorphism
                                • rheumatoid arthritis

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