Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn's disease treated with infliximab.
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.
Mascheretti
S
S
1st Medical Department, Christian-Albrechts-University, Kiel, Germany.
Hampe
J
J
Kühbacher
T
T
Herfarth
H
H
Krawczak
M
M
Fölsch
U R
UR
Schreiber
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods / Q000706:statistics & numerical data; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D018709:Statistics, Nonparametric
D000911:Antibodies, Monoclonal; D018124:Receptors, Tumor Necrosis Factor; D000069285:Infliximab