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Genome-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.    Methods  To 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.    Results  Weak 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.    Conclusions  Our 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.

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