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

被引：119

作者：

Mascheretti S. ^{[1
]}

Hampe J. ^{[1
]}

Kühbacher T. ^{[1
]}

Herfarth H. ^{[2
]}

Krawczak M. ^{[3
,4
]}

Fölsch U.R. ^{[1
]}

Schreiber S. ^{[1
]}

机构：

[1] 1st Department of Medicine, Christian-Albrechts-University, Kiel

[2] University of Regensburg, 1st Department of Medicine, Regensburg

[3] Institute of Medical Genetics, University of Wales College of Medicine, Cardiff

[4] Institute for Medical Informatics and Statistics, Christian-Albrechts-University, Kiel

来源：

The Pharmacogenomics Journal | 2002年 / 2卷 / 2期

关键词：

Autoimmunity; Clinical trial; Crohn's disease; Inflammatory bowel disease; Infliximab; TNF;

D O I：

10.1038/sj.tpj.6500091

中图分类号：

学科分类号：

摘要：

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.

引用

页码：127 / 136

页数：9

共 52 条

[1]

Spielman R.S., McGinnis R.E., Ewens W.J., The transmission/disequilibrium test detects cosegregation and linkage, Am. J. Hum. Genet, 54, pp. 559-560, (1994)

[2]

Hampe J., Wienker T., Nurnberg P., Schreiber S., Mapping genes for polygenic disorders: Consideration for study design in the complex trait of inflammatory bowel disease, Hum. Hered, 50, pp. 91-101, (2000)

[3]

Summers R.W., Switz D.M., Sessions J.T., Becktel J.M., Best W.R., Kern F., Et al., National Cooperative Crohn's Disease Study: Results of drug treatment, Gastroenterology, 77, pp. 847-869, (1979)

[4]

Malchow H., Ewe K., Brandes J.W., Goebell H., Ehms H., Sommer H., Et al., European Cooperative Crohn's Disease Study (ECCDS): Results of drug treatment, Gastroenterology, 86, pp. 249-266, (1984)

[5]

Schreiber S., Nikolaus S., Hampe J., Hamling J., Koop I., Lochs H., Et al., Tumor necrosis factor alpha and interleukin 1-beta in relapse of Crohn's disease, Lancet, 353, pp. 459-461, (1999)

[6]

Reinecker H.C., Steffen M., Witthoeft T., Pflueger I., Schreiber S., MacDermott R.P., Et al., Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease, Clin. Exp. Immunol, 94, pp. 174-181, (1993)

[7]

Targan S.R., Hanauer S.B., Van Deventer S.J., Mayer L., Present D.H., Braakman T., Et al., A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease, N. Engl. J. Med, 337, pp. 1029-1035, (1997)

[8]

Stack W.A., Mann S.D., Roy A.J., Heath P., Sopwith M., Freeman J., Et al., Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease, Lancet, 349, pp. 521-524, (1997)

[9]

Kempeni J., Preliminary results of early clinical trails with the fully human anti-TNFalpha monoclonal antibody D2E7, Ann. Rheum. Dis, 58, pp. 170-172, (1999)

[10]

Bickston S.J., Lichtenstein G.R., Arsenau K.O., Cohen R.B., Cominelli F., The relationship between infliximab treatment and lymphoma in Crohn's disease, Gastroenterology, 117, pp. 1433-1437, (1999)

← 1 2 3 4 5 6 →