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Item does not contain fulltext OBJECTIVE: In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. METHODS: We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. RESULTS: We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment = 0.15, based on phenotype permutations). CONCLUSION: Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.

Tumour necrosis factor (TNF)-alpha is an important pro-inflammatory cytokine that has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The promoter TNF-857 C-->T single nucleotide polymorphism (SNP) is functional through the binding to the transcription factor octamer transcription factor-1 (OCT-1). In order to investigate the frequency of this SNP in Israeli Jewish IBD patients, we analysed a cohort of well-characterized patients, 153 with Crohn's disease (CD) and 78 with ulcerative colitis (UC) and 188 healthy controls individually matched for age, sex and ethnicity. Forty-one per cent of the patients were of Ashkenazi and 48% were of non-Ashkenazi background. The remaining 11% were of mixed Ashkenazi-non-Ashkenazi background. Patients and controls were genotyped for the TNF-857 SNP by Taqman technology. Stratification for the CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC mutations took place in 136 CD patients. Carrier frequency of TNF-857T between CD and controls (36% vs. 40%; P = 0.556; OR: 1.18, 95% CI 0.74-1.88), or between UC and controls (41% vs. 37%; P = 0.743; OR: 0.85, 95% CI 0.45-1.62) did not differ significantly. Neither did stratifying for the presence of at least one of the common CARD15 mutations result in a significant difference between CD and controls. No associations were found between TNF-857T and CD phenotype as defined by the Vienna classification, perianal disease or extra-intestinal disease irrespective of CARD15 carrier status. In conclusion, it appears that TNF-857 SNP does not contribute to susceptibility of IBD, neither does it define the phenotype of CD in Israeli Jewish IBD patients.

Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (▵DAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ▵DAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.