Background/Purpose: The TNFα inducible protein 3 (TNFAIP3=A20) is an important regulatory protein for the inhibition of NFkB activation in TNFaR and TLR pathways. It belongs to a group of genes that have been described as regulated differentially in mononuclear blood cells from patients with rheumatoid arthritis treated with TNFα-blockers early in the course of treatment in association to the clinical outcome. Recently published studies demonstrated that sequence variations in the TNFAIP3 gene are associated with the risk for several autoimmune diseases including RA, SLE and psoriasis. It was the aim of our study to analyze the frequency of two independent SNPs (rs583522 T/C intron, and rs2230926 T/G, exon 3) in the TNFAIP3 gene in CCP-antibody positive and negative RA patients and to determine their potential role as a predictive biomarker for therapy outcome of anti-TNFα treatment.

Methods: 423 RA patients with high disease activity and 93 healthy controls were included in the study. Genotyping was performed with pre-designed TaqMan assays for rs583522 and rs2230926 in 5µl reaction mixtures containing 10 ng genomic DNA. HLA-Genotyping was performed using the HLA-DRB1 Shared epitope reverse Hybridization Kit (AID GmbH Germany). CCP-antibody levels were determined with the CCP-2 assay (Menarini, Italy). Disease activity and therapy response were assessed according to the EULAR criteria.

Results: For the intronic SNP rs583522 (T/C) a significant lower frequency of the minor allele was observed in RA patients compared to controls (p=0.014), no significant differences were seen in the allele frequency between CCP-antibody positive and negative RA patients nor in association to the shared epitope encoding alleles. A higher frequency of the minor allele (G) was found in RA patients compared to controls for rs2230926 (T/G), without reaching statistical significance (p=0.160). CCP-antibody negative patients had a higher frequency of the T/G genotype compared to CCP-antibody positive patients. In contrast to the entire RA group, the subgroup of CCP-antibody negative RA patients had a significant higher allele frequency of the minor allele compared to healthy controls (p=0.042). Disease activity was comparable for the three genotypes of the intronic SNP. For rs2230926 a significant higher disease activity was observed in T/T genotype in contrast to T/G genotype (DAS28 5.78+0.08 vs 5.07+0.31, mean+SEM). No differences were found in the genotype distribution for both SNPs between TNF-blocker responders and non-responders.

Conclusion: Our data confirm earlier reports  of an association of the non-synonymous polymorphism rs2230926 in exon 3 resulting in an amino acid substitution Phe/Cys with the risk for RA, particularly for CCP-negative disease. The association of the intronic SNP rs583522 with the risk for RA has not been described before. A predictive importance of the analyzed polymorphisms for therapy outcome of TNF-blocker therapies could not be observed. Due to the low frequency of the minor allele of rs2230926 data have to be considered preliminary and confirmed in larger cohorts.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-tnfaip3-gene-polymorphisms-with-the-risk-for-ra-and-prediction-of-therapy-outcome-of-tnf%ce%b1-blocker-treatment/