Open Access Highly Accessed Research article

A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity

Lina M Olsson1*, Anna-Karin Lindqvist12, Henrik Källberg3, Leonid Padyukov4, Harald Burkhardt5, Lars Alfredsson3, Lars Klareskog4 and Rikard Holmdahl1

Author Affiliations

1 Medical Inflammation Research, Lund University, BMC I11, 221 84, Lund, Sweden

2 Cartela AB, Box 709, SE-220 07 Lund Sweden

3 Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden

4 Rheumatology Unit, Department of Medicine, Karolinska Institutet, 171 76, Stockholm, Sweden

5 Division of rheumatology, Johann Wolfgang Goethe University, Theodor-Stern-Kai, 60596 Frankfurt am Main, Germany

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Arthritis Research & Therapy 2007, 9:R98  doi:10.1186/ar2299

Published: 26 September 2007

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.