The inﬂuence of a TNF gene polymorphism on the severity of rheumatoid arthritis in the Brazilian Amazon Antonio Luiz Boechat a,b,⇑ , Narjara de Oliveira Boechat a , Mauricio Morishi Ogusku c , Mariana Raposo Alencar a , Themis da Costa Abensur d , José Cardoso Neto d , Leilian de Souza Amorim a , Lívia Moura de Oliveira a , Aya Sadahiro b , Maria Cristina Dos-Santos b a Clínica de Artrite Reumatoide, Hospital Adriano Jorge, Manaus, Brazil b Laboratório de Imunologia, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Brazil c Laboratório de Micobacteriologia, Instituto Nacional de Pesquisas da Amazônia (INPA), Brazil d Departamento de Estatística, Instituto de Ciências Exatas, Universidade Federal do Amazonas, Brazil article info Article history: Received 27 June 2012 Received in revised form 15 August 2012 Accepted 22 November 2012 Available online xxxx Keywords: TNF -308 gene polymorphism Rheumatoid arthritis Extra-articular disease Anti-TNF drugs Biologics abstract Purpose: The aim of this study was to investigate the inﬂuence of the TNF -308 G/A polymorphism in the promoter region of the tumor necrosis factor-a gene on the susceptibility and severity of rheumatoid arthritis (RA) in individuals from the Brazilian Amazon. Methods: A total of 323 individuals—192 healthy controls without arthritis and 131 individuals suffering from arthritis—were genotyped for this polymorphism using a methodology based on PCR-RFLP. Results: The frequency of the A allele (TNF2) in rheumatoid arthritis sufferers was not signiﬁcantly higher than in the controls (p = 0.926; OR = 0.97; conﬁdence interval 0.54–1.76). However, using a logistic regression model, when the patients were stratiﬁed according to whether the manifestations were pre- ponderantly articular or systemic, there was a strong association between the TNF2 allele and systemic arthritis (p = 0.001; OR = 5.89; conﬁdence interval = 1.98–17.5) as well as the use of anti-TNF immuno- therapy (p = 0.023; OR = 1.10; conﬁdence interval = 1.00–1.14). The main factors that were found to inﬂu- ence the risk of extra-articular disease were age greater than or equal to 60 years (p = 0.008; OR = 4.06; conﬁdence interval = 1.45–11.38), disease duration greater than 10 years (p = 0.031; OR = 3.10; conﬁ- dence interval = 1.11–8.63) and positive rheumatoid factor (p = 0.035; OR = 2.07; conﬁdence inter- val = 1.05–4.09). Conclusions: These results suggest that the TNF2 allele is associated with the more serious forms of the disease in individuals from the Brazilian Amazon but not with a risk for developing RA. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Rheumatoid arthritis (RA) is a chronic synovial inﬂammatory arthropathy affecting around 1% of the world’s population [1] and a serious pathological condition that can lead to incapacitation and reduced life expectancy compared with the normal population [2]. Studies in Brazil indicate that the prevalence of RA in the pop- ulation is between 0.2% and 1% [3]. Although the etiology of RA has yet to be clariﬁed, it has been established that genetic factors play a role in susceptibility to this condition. Familial aggregation, multiple genetic linkage and asso- ciation studies have demonstrated the genetic basis of the disease [4,5]. Several genetic associations have been found, especially in the human leukocyte antigen (HLA) region, with HLA loci showing the strongest genetic association with RA [5–8]. Tumor necrosis factor (TNF) is a potent pleiotropic proinﬂam- matory cytokine produced mainly by macrophages. Elevated levels of this cytokine have been implicated in various proinﬂammatory conditions [9]. In RA, proinﬂammatory cytokines such as TNF-a, interleukin-1 (IL-1) and interleukin-6 (IL-6) are highly expressed and very abundant in synovial ﬂuid, as are the anti-inﬂammatory cytokines IL-10 and TGF-b. The latter, however, are not present in sufﬁciently high concentrations to suppress synovitis [10–13]. It is against this background that genetic polymorphisms of proin- ﬂammatory cytokines can play an important role by amplifying the chain of inﬂammatory events triggered by the disease. TNF stimu- lates secretion of cytokines, increases expression of adhesion mol- ecules in the endothelium and promotes neutrophil activation and migration. In addition, it has co-stimulatory effects on T-cell acti- vation and antibody production by B-lymphocytes [12]. 1043-4666/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2012.11.020 ⇑ Corresponding author. Address: Laboratório de Imunologia, Instituto de Ciên- cias Biológicas, Universidade Federal do Amazonas, Av. General Rodrigo Otávio Jordão Ramos, Manaus 3000, CEP 69077-000, Brazil. Tel.: +55 92 3305 4271. E-mail address: alboechat@ufam.edu.br (A.L. Boechat). Cytokine xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Boechat AL et al. The inﬂuence of a TNF gene polymorphism on the severity of rheumatoid arthritis in the Brazilian Ama- zon. Cytokine (2013), http://dx.doi.org/10.1016/j.cyto.2012.11.020