Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis

Objective

Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically. The aim of the present study was to independently replicate 3 recently described RA susceptibility loci, STAT4, IL2/IL21, and CTLA4, in a large Dutch case–control cohort, and to perform a meta‐analysis of all published studies to date and investigate the relevance of the findings in clinically well‐defined subgroups of RA patients with or without autoantibodies.

Methods

The STAT4, IL2/IL21, and CTLA4 gene polymorphisms (rs7574865, rs6822844, and rs3087243, respectively) were genotyped in 877 RA patients and 866 healthy individuals. A meta‐analysis of all published studies of disease association with these polymorphisms was performed using the Mantel‐Haenszel fixed‐effects method.

Results

An association of STAT4, IL2/IL21, and CTLA4 with RA was detected in Dutch patients (odds ratio [OR] 1.19 [P = 0.031], OR 0.84 [P = 0.051], and OR 0.87 [P = 0.041], respectively). Results from the meta‐analysis confirmed an association of all 3 polymorphisms with RA in Caucasians (OR 1.24 [P = 1.66 × 10⁻¹¹], OR 0.78 [P = 5.6 × 10⁻⁵], and OR 0.91 [P = 1.8 × 10⁻³], respectively). The meta‐analysis also revealed that STAT4 predisposed to disease development equally in patients with autoantibodies and those without autoantibodies, and that CTLA4 enhanced the development of anti–citrullinated protein antibody (ACPA)–positive RA as compared with ACPA‐negative RA.

Conclusion

Our results replicate and firmly establish the association of STAT4 and CTLA4 with RA and provide highly suggestive evidence for IL2/IL21 loci as a risk factor for RA. Given the strong statistical power of our meta‐analysis to confirm a true‐positive association, these findings provide considerable support for the involvement of CTLA4 in distinct subsets of RA patients.