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 Olsson,Harald Burkhardt,Leonid Padyukov,Henrik Källberg,Anna-Karin Lindqvist,Rikard Holmdahl,Lars Klareskog,Lars Alfredsson

doi:10.1186/ar2299

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.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to erosion and deformation of the joints
Because of the complex interplay between the proteins of the NOX complex, it is likely that genetic changes in any of the genes could have the same effect on reactive oxygen species (ROS) production, as is seen for Ncf1 in rats
Fifty-one single nucleotide polymorphisms were successfully genotyped in a Swedish rheumatoid arthritis cohort To investigate the genes in the NOX complex for association with RA, 67 SNPs evenly dispersed in the five candidate genes (Table 1) were selected from the HapMap genome browser and dbSNP (National Center for Biotechnology Information; Additional file 1)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to erosion and deformation of the joints. Despite much effort to identify arthritis causing genes, only few genetic loci have been confirmed to be associated with RA, among which are the human leucocyte antigen (HLA) locus and the protein tyrosine phosphatase non-receptor 22 gene (PTPN22) [2,3,4]. RA is a heterogeneous disease with symptoms and disease progression that vary between patients. The heterogeneity of the symptoms in RA probably mirrors the CCP = cyclic citrullinated peptide; CEPH = Centre d'Etude du Polymorphisme Humain; CI = confidence interval; EIRA = Epidemiological Investigation of Rheumatoid Arthritis; HWE = Hardy-Weinberg equilibrium; NOX = NADPH oxidase; OR = odds ratio; RA = rheumatoid arthritis; RF = rheumatoid factor; ROS = reactive oxygen species; SE = shared epitope; SNP = single nucleotide polymorphism

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