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THU0276 Importance of TNFAIP3 Gene Polymorphism for RA Susceptibility and Prediction of Therapy Outcome of Tnf-Blocker Therapy
  1. S. Drynda,
  2. M. Gloetzner,
  3. J. Reinecke,
  4. J. Kekow
  1. Clinic of Rheumatology, University of Magdeburg, Vogelsang, Germany

Abstract

Background TNFα inducible protein 3 (TNFAIP3) belongs to a group of genes that were found to be differentially regulated in PBMC of anti-TNFα treated patients with rheumatoid arthritis (RA) with different clinical outcome (Koczan et. al Arthritis Res Ther. 2008; 10(3): R50). It is an important regulatory protein for the inhibition of NFκB activation in TNFαR and TLR pathways. Recent studies showed different risk loci in the TNFAIP3 gene associated with different autoimmune diseases such as RA, SLE and psoriasis.

Objectives In our study we analysed the frequency of two independent SNPs in the TNFAIP3 gene on chromosome 6 (rs583522, T/C intron, and rs2230926, T/G, exon 3) in ACPA positive and negative RA patients vs. healthy controls and their association to disease activity and clinical outcome of TNFα-blocker therapy.

Methods In this study 428 RA patients and 93 healthy controls (HC) were genotyped. Genotyping was performed with pre-designed TaqMan assays in 5μl reaction mixtures containing 10 ng genomic DNA. HLA-genotyping was performed using the HLA-DRB1 Shared Epitope (SE) reverse Hybridization Kit (AID GmbH, Germany). For analysing ACPAs the CCP-2 assay (Menarini, Italy) was used. Disease activity and therapy response were assessed according to the EULAR criteria. Gene expression levels of TNFAIP3, IL-1β, TNFα, IL-6 in PBMC from selected RA patients before initiation of therapy were determined by RT- PCR.

Results For the intronic SNP rs583522 (T/C) a significant lower frequency of the minor allele was observed in RA patients compared to HC (p=0.014), no significant differences were seen in the allele frequency between ACPA positive and negative RA patients nor in association to the SE. For rs2230926 a higher frequency of the minor allele (G) was found in RA patients compared to controls 3.65% and 1.6%, resp., without reaching statistical significance (p=0.160). Differences were found between SE positive and negative as well as for ACPA positive and negative RA patients. SE and ACPA negative patients had a higher frequency of the minor G allele compared to ACPA positive patients. In contrast to the entire RA group, the subgroup of ACPA negative RA patients had a significant higher allele frequency of the minor allele compared to healthy controls (p=0.042).

Gene expression levels of TNFAIP3, IL-1β, TNFα, IL-6 in PBMC of selected RA patients did not differ significantly between different genotypes of both SNPs.

Disease activity was comparable for the three genotypes of the intronic SNP. For rs2230926 a significant higher disease activity was observed in T/T in contrast to T/G (ESR mm/h 45,5±1.8 vs. 35.6±5.5, and DAS28 5.8±0.1 vs 5.1±0.3, mean ± SEM). No differences were found in the genotype distribution between TNF-blocker responders and non-responders for both polymorphisms.

Conclusions Our data confirm the association of the non-synonymous polymorphism rs2230926 in exon 3 of the TNFAIP3 gene, resulting in an amino acid substitution Phe/Cys, with the risk for RA, particularly for ACPA negative disease. The association of the intronic SNP rs583522 with the risk for RA has not been described before.

A functional importance of the analysed polymorphisms could not be observed in terms of differential gene regulation or therapy response to TNFα-blockers.

Due to the low frequency of the minor allele of rs2230926 data have to be considered preliminary and confirmed in larger cohorts.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.5167

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