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

Pharmacogenomics J. 2002;2(2):127-36. doi: 10.1038/sj.tpj.6500091.


Infliximab (anti-TNF-alpha 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-alpha 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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Monoclonal / therapeutic use*
  • Chi-Square Distribution
  • Cohort Studies
  • Crohn Disease / drug therapy*
  • Crohn Disease / genetics*
  • Female
  • Gene Frequency / genetics
  • Humans
  • Infliximab
  • Male
  • Middle Aged
  • Mutation / genetics
  • Pharmacogenetics / methods
  • Pharmacogenetics / statistics & numerical data
  • Polymorphism, Genetic / genetics
  • Prospective Studies
  • Receptors, Tumor Necrosis Factor / genetics*
  • Statistics, Nonparametric


  • Antibodies, Monoclonal
  • Receptors, Tumor Necrosis Factor
  • Infliximab