Association of the CCR5 gene with juvenile idiopathic arthritis

Abstract

The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (P(trend)=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66-0.94). The meta-analysis of all published case-control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73-0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA.

Figure 1

Meta-analysis of three studies of the CCR5Δ32 variant. Meta-analysis of UK, US and Norwegian JIA cohorts for the CCR5 gene. Forest plot displaying odds ratios and 95% confidence intervals for each of the studies and the weighting for each study according to sample size. The combined OR from the three studies is displayed as a diamond with the peaks denoting the upper and lower limits of the confidence intervals. Values below 1 depict a negative (protective) association. The Breslow-Day test was performed to test for heterogeneity between the two studies, with a significant P-value suggesting heterogeneity between studies. The combined P-value is displayed below the heterogeneity P-value.