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Abstract Number: 1186

A Single Nucleotide Polymorphism of Tumor Necrosis Factor Receptor-Associated Factor 1 Predicts Clinical Response to Anti-Tumor Necrosis Factor Treatments in Japanese Patients with Rheumatoid Arthritis

Tetsuya Nishimoto1, Noriyuki Seta2, Ryusuke Anan2, Tatsuya Yamamoto2, Yuko Kaneko3, Masataka Kuwana4 and Tsutomu Takeuchi5, 1Department of Medicine, Medical University of South Carolina, Charleston, SC, 2Department of Internal Medicine, Keio university, Tokyo, Japan, 3Dept of Internal Medicine, Keio Univ School of Medicine, Shinjuku-ku, Japan, 4Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, 5Keio University School of Medicine, Tokyo, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, polymorphism and rheumatoid arthritis (RA)

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Session Information

Session Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Recent genome-wide association studies have disclosed several single nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA) susceptibility. Among them, it is reported that the SNP of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) (+16860A/G) is associated with pathophysiology of RA in both Asians and Caucasians. Therefore, in this study, we assessed the usefulness of TRAF1 genotyping as a genetic predictor of the response to anti-TNF treatments in Japanese RA patients, and examined an underlying mechanism of the association between TRAF1 polymorphism and the clinical response to anti-TNF treatments.

Methods: TRAF1 (+16860A/G) was genotyped using TaqMan® SNP genotyping assay. 101 Japanese RA patients were enrolled, and retrospectively analyzed the association between the SNP and the clinical response to treatment with anti-TNF drugs as a first biologic agent, such as infliximab, etanercept and adalimumab. The clinical response was assessed by the 28-joint Disease Activity Score (DAS28)-ESR response criteria at 24 weeks after the initiation of anti-TNF treatments. To investigate the effect of the SNP on the expression of TRAF1, CD4+, CD8+, CD14+ or CD19+ cells were isolated using magnetic activated cell sorting from peripheral blood mononuclear cells obtained from healthy subjects with AA (n=6), AG (n=6), or GG (n=3) genotype, and then the mRNA expression of TRAF1 in CD4+, CD8+, CD14+ or CD19+ cells were evaluated by TaqMan™ quantitative RT-PCR. The expression of TRAF1 was evaluated by intracellular staining in combination with staining for CD4, CD8, CD14 or CD19 using flowcytometry.

Results: In 101 RA patients received anti-TNF treatments, 63 (62.4%), 28 (27.7%), and 10 (9.9%) patients achieved good, moderate, and no response, respectively. There was no statistical difference in DAS28-ESR at baseline among each patient group with AA, AG, or GG genotype. However, the relative change in DAS28-ESR from baseline to 24 weeks after the initiation of anti-TNF treatments tended to be decreased in patients with GG genotype compared to those with AA or AG genotype (1.27 versus 2.16, P=0.057 ). GG genotype was more frequently detected in patients with no response compared to those with good or moderate response (30.0% versus 5.5%, P=0.031, OR 7.4, 95%CI 1.5-37.5). Patients with no response more frequently possessed G allele than those with good or moderate response (55.0% versus 25.8%, P=0.006, OR 3.5, 95%CI 1.4-9.0). Quantitative RT-PCR revealed that mRNA for TRAF1 was highly expressed in CD8+ or CD14+ cells with AG or GG genotype compared to those with AA genotype (P=0.045). Flowcytometric analysis also showed that the expression of TRAF1 tended to be increased  in CD14+ cells with AG or GG genotype compared to those with AA genotype (p = 0.09).

Conclusion: TRAF1 (+16860A/G) is possibly useful for prediction of the clinical response to anti-TNF treatments, and may contribute to resistance to anti-TNF treatments in RA patients with G allele via increased expression of TRAF1 in circulating inflammatory cells.


Disclosure:

T. Nishimoto,
None;

N. Seta,
None;

R. Anan,
None;

T. Yamamoto,
None;

Y. Kaneko,
None;

M. Kuwana,
None;

T. Takeuchi,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-single-nucleotide-polymorphism-of-tumor-necrosis-factor-receptor-associated-factor-1-predicts-clinical-response-to-anti-tumor-necrosis-factor-treatments-in-japanese-patients-with-rheumatoid-arthriti/

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