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Open Access Research article

Meta-analysis identified the TNFA -308G > A promoter polymorphism as a risk factor for disease severity in patients with rheumatoid arthritis

Erik JM Toonen1, Pilar Barrera2, Jaap Fransen2, Arjan PM de Brouwer3, Agnes M Eijsbouts4, Pierre Miossec5, Hubert Marotte5, Hans Scheffer3, Piet LCM van Riel2, Barbara Franke3 and Marieke JH Coenen3*

Author affiliations

1 Department of Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein-zuid 10, Nijmegen, 6525 GA, The Netherlands

2 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-zuid 10, Nijmegen, 6525 GA, The Netherlands

3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Geert Grooteplein-zuid 10, Nijmegen 6525 GA, The Netherlands

4 Department of Rheumatology, St Maartenskliniek, Hengstdal 3, Ubbergen, 6574 NA, The Netherlands

5 Clinical Immunology Unit, Departments of Immunology and Rheumatology, hospital Edouard Herriot, Place 5 d'Arsonval, 69437, Lyon, France

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Citation and License

Arthritis Research & Therapy 2012, 14:R264  doi:10.1186/ar4110

Published: 7 December 2012

Abstract

Introduction

The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).

Methods

A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.

Results

Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.

Conclusions

Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.