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.

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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/