Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-κB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility

Rebeca Dieguez-Gonzalez,Federico Navarro,Javier Narvaez,Alejandro Balsa,Rafael Caliz,Ana Ortiz,Juan J Gomez-Reino,Arturo R De La Serna,Jose L Marenco,Benjamin Fernandez-Gutierrez,Luis Carreño,Juan D Cañete,Francisco J Blanco,Antonio Gonzalez,Manuel Calaza,Gabriel Herrero-Beaumont,Eva Perez-Pampin,Jose L Pablos

doi:10.1186/ar2650

Abstract

IntroductionGenome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes. TNFAIP3, an RA candidate gene, flanks this region, and polymorphisms in both the TNFAIP3 gene and the intergenic region are associated with systemic lupus erythematosus. We hypothesized that there is a similar association with RA, including polymorphisms in TNFAIP3 and the intergenic region.MethodsTo test this hypothesis, we selected tag-single nucleotide polymorphisms (SNPs) in both loci. They were analyzed in 1,651 patients with RA and 1,619 control individuals of Spanish ancestry.ResultsWeak evidence of association was found both in the 6q23 intergenic region and in the TNFAIP3 locus. The rs582757 SNP and a common haplotype in the TNFAIP3 locus exhibited association with RA. In the intergenic region, two SNPs were associated, namely rs609438 and rs13207033. The latter was only associated in patients with anti-citrullinated peptide antibodies. Overall, statistical association was best explained by the interdependent contribution of SNPs from the two loci TNFAIP3 and the 6q23 intergenic region.ConclusionsOur data are consistent with the hypothesis that several RA genetic factors exist in the 6q23 region, including polymorphisms in the TNFAIP3 gene, like that previously described for systemic lupus erythematosus.

Highlights

Genome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes
tumor necrosis factor-α-induced protein 3 (TNFAIP3) locus Six tagSNPs were sufficient to cover the TNFAIP3 gene and 20 kb of flanking sequences to either side [see Table S2 and Additional data file 1]. Genotypes of these tagSNPs were obtained with a 99.1% call rate, and they were in Hardy-Weinberg equilibrium (HWE) except for the rs629953 single nucleotide polymorphisms (SNPs), which was excluded from further analysis
Multivariate analysis combining haplotype #5 and rs582757 SNP genotypes revealed that any of them could account for the association with RA and that the two association signals were not independent [see Table S3 in Additional data file 1]

Summary

Introduction

Genome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes. The first GWA studies in RA were readily able to confirm the two clearest RA genetic factors – in the human leukocyte antigen region and in the PTPN22 gene [1,2,3]. Such studies have found other significant associations. Two single nucleotide polymorphisms (SNPs) in 6q23, namely rs6920220 and rs13207033 (or its perfect surrogate rs10499194), have exhibited peak association with RA in an independent manner [2] This finding has been interpreted as indicating the involvement of multiple genetic variants in RA susceptibility [2]. This gene is an excellent candidate for such an effect because it is a feedback negative regulator of tumor necrosis factor signaling through nuclear factor-κB (NF-κB) [8,9,10]

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Results

Discussion

Conclusion