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Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab

Abstract

Infliximab (anti-TNF-α monoclonal antibody) induces remission in 30–40% of Crohn's disease patients. Treatment response is a stable trait. Two cohorts from independent, prospective clinical trials of infliximab in Crohn's disease were studied. Hypotheses were generated in an exploratory cohort (n = 90) and then tested in a confirmatory cohort (n = 444), using a statistical design, which is stable against type 1 and type 2 errors. In the exploratory cohort, the mutant 196Arg allele of TNFR-II (exon 6 polymorphism) and a novel silent polymorphism in exon 2 of TNFR-II were associated with lack of response to infliximab (83.3% in homozygote mutant 196 Arg patients vs 36.9% in heterozygotes and wild-type homozygotes (P = 0.036) and 85.7% in homozygote mutant exon 2 patients vs 36.1% (P = 0.01), respectively). None of the homozygote mutant individuals (0/6) achieved clinical remission, whereas the remission rate was 35.7% (30/84) in wild-type homozygotes and heterozygotes. In the large second cohort, the observed genotype–phenotype associations were not replicated. Other polymorphisms (TNF-α promoter −238, −308, −376, −857, −1031, TNF-R-I −609, +36 (exon 1), TNF-R-II 1663, 1690 (3′-UTR)) were not associated with treatment response in both cohorts (P > 0.5). None of the polymorphisms was associated with refractory Crohn's disease itself when compared to healthy controls. In a two-cohort study, a series of polymorphisms in the TNF, the TNF-R-I and in the TNF-R-II genes could be thoroughly excluded as pharmacogenetic markers for a treatment response to infliximab and as etiologic factors for Crohn's disease, respectively. The discrepancy between the two cohorts observed for the TNF-R-II exon 6 and exon 2 polymorphism may point to a weak effect on treatment response but also serves to illustrate the need for a sequential exploratory/confirmatory design in pharmacogenetic studies.

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Acknowledgements

This work was supported by grants from the ‘Deutsche Forschungsgemeinschaft’ (SFB 415, FOR 423), through a Competence Network from the German Ministry for Education and Research (BMBF), a Training and Mobility of Researchers Grant from the European Commission (TMR), and by direct contributions from Centocor Inc. The authors are indebted to the clinical investigators who have contributed patients and follow-ups in the multi-center trials. The contribution of Nicolaos Sfikas in the design and the statistical evaluation of typing data is gratefully acknowledged. The authors are grateful to Alan Olson and Gregory Harriman for critical discussion of the design, protocol and the results and to B Weihang for statistical advice.

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Mascheretti, S., Hampe, J., Kühbacher, T. et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab. Pharmacogenomics J 2, 127–136 (2002). https://doi.org/10.1038/sj.tpj.6500091

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