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.
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 RApatients with or without autoantibodies. METHODS: The STAT4, IL2/IL21, and CTLA4 gene polymorphisms (rs7574865, rs6822844, and rs3087243, respectively) were genotyped in 877 RApatients 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 RApatients.
Authors: Amit K Maiti; Xana Kim-Howard; Parvathi Viswanathan; Laura Guillén; Adriana Rojas-Villarraga; Harshal Deshmukh; Haner Direskeneli; Güher Saruhan-Direskeneli; Carlos Cañas; Gabriel J Tobön; Amr H Sawalha; Alejandra C Cherñavsky; Juan-Manuel Anaya; Swapan K Nath Journal: Arthritis Rheum Date: 2010-02
Authors: Dalia El-Lebedy; Hala Raslan; Alshaymaa Ibrahim; Ingy Ashmawy; Shereen Abd El-Aziz; Asmaa M Mohammed Journal: Clin Rheumatol Date: 2017-04-19 Impact factor: 2.980
Authors: Ma de Jesús Durán-Avelar; Norberto Vibanco-Pérez; Raquel Rocío Hernández-Pacheco; América Del Carmen Castro-Zambrano; Liliana Ortiz-Martínez; José Francisco Zambrano-Zaragoza Journal: Clin Rheumatol Date: 2016-05-28 Impact factor: 2.980
Authors: Darren Plant; Edward Flynn; Hamdi Mbarek; Philippe Dieudé; François Cornelis; Lisbeth Arlestig; Solbritt Rantapää Dahlqvist; George Goulielmos; Dimitrios T Boumpas; Prodromos Sidiropoulos; Julia S Johansen; Lykke M Ørnbjerg; Merete Lund Hetland; Lars Klareskog; Andrew Filer; Christopher D Buckley; Karim Raza; Torsten Witte; Reinhold E Schmidt; Jane Worthington Journal: Ann Rheum Dis Date: 2010-05-24 Impact factor: 19.103
Authors: Jade E Hollis-Moffatt; Michael Chen-Xu; Ruth Topless; Nicola Dalbeth; Peter J Gow; Andrew A Harrison; John Highton; Peter B B Jones; Michael Nissen; Malcolm D Smith; Andre van Rij; Gregory T Jones; Lisa K Stamp; Tony R Merriman Journal: Arthritis Res Ther Date: 2010-06-16 Impact factor: 5.156