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=1.66x10(-11)], OR 0.78 [P=5.6x10(-5)], and OR 0.91 [P=1.8x10(-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.