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

Abstract

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. ], 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.

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

“…The SNP rs6822844 for IL-2/IL-21 was investigated for associations with the disease and for associations with autoantibody status in a Dutch RA cohort. IL-2/IL-21 rs6822844 showed a clear trend toward association with RA [65] . The KIAA1109-TENR-IL2-IL21 region has been associated with a wide variety of autoimmune diseases like type 1 diabetes (T1D) [66] , ulcerative colitis [67] , Crohn's disease [68] , celiac disease, Graves' disease (GD) [66] , systemic lupus erythematosus (SLE) [69] , psoriatic arthritis [70] , and juvenile idiopathic arthritis [71] .…”

Diagnostic Value of Interleukin 21 and Carcinoembryonic Antigen Levels in Malignant Pleural Effusions

“…Care was taken to make sure that the patients matched the diagnostic criterias and didn't suffer from chronic diseases such as chronic viral infections (Elsaesser et al, 2009), SLE (Sarra et al, 2010), Rheumatoid Arthritis (Daha et al, 2009), Psoriasis (Liu et al, 2008) and Inflammatory bowel diseases (Liu et al, 2009). Written consent was obtained from all the patients concerned in order to perform this study.…”

Pharmacogenetics of rheumatoid arthritis: Potential targets from susceptibility genes and present therapies

“…While other polymorphisms within the CTLA4 gene appear to be associated with RA, [78][79][80] an GA SNP in the 3′ untranslated region (CT60; rs3087243) has received a more thorough investigation, especially in European populations. 37,52,[80][81][82] Although previous case-control studies in various populations have suggested a possible association of CTLA4 alleles with RA, the results of these studies are often inconclusive and are sometimes contradictory. A large cohort (n cases/controls = 2,370/1,757) from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections, provided support for an association of CTLA4 (CT60 allele) with the development of RA, but only in the NARAC cohort (OR = 1.1, 95% CI: 1.0-1.2; P = 0.004).…”