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.
- copy number
- rheumatoid arthritis
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