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=1.66x10(-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.


CONCLUSIONS
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.
Daha
Nina A
NA
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Kurreeman
Fina A S
FA
Marques
Rute B
RB
Stoeken-Rijsbergen
Gerrie
G
Verduijn
Willem
W
Huizinga
Tom W J
TW
Toes
René E M
RE
D000917:Antibody Formation; D015703:Antigens, CD / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies; D060908:CTLA-4 Antigen; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics*; D000098546:Interleukin-21
D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D007378:Interleukins; D050797:STAT4 Transcription Factor; D000098546:Interleukin-21