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The TNF/ADAM 17 system: implication of an ADAM 17 haplotype in the clinical response to infliximab in Crohn's disease

Dideberg, Vincianea; Théâtre, Emiliea; Farnir, Frédéricc; Vermeire, Séverined; Rutgeerts, Pauld; Vos, Martine Dee; Belaiche, Jacquesb; Franchimont, Denisf; Gossum, André Vanf; Louis, Edouardb *; Bours, Vincenta *

doi: 10.1097/01.fpc.0000230117.26581.a4

Infliximab, a chimeric anti-tumour necrosis factor (TNF)-α antibody induces a clinical response in 70% of Crohn's disease patients and the response to infliximab therapy could be partially determined by genetic factors. The implication of both transmembrane and soluble forms of the TNF-α in the mechanism of action of infliximab has been demonstrated. The aim of our work was first to perform a complete study of TNF variants role in the response to infliximab in Crohn's disease. Secondly, considering the role of ADAM 17 in TNF-α shedding, the ADAM 17 locus was also studied. The response to infliximab was evaluated in 222 Caucasian Crohn's disease patients with a luminal (n=160) or fistulizing (n=62) form of the disease. Clinical and biological response evaluation was based on the Crohn's Disease Activity Index score and C-reactive protein level evolutions, respectively. The entire TNF gene was sequenced on the complete cohort. Twelve single nucleotide polymorphisms spanning the ADAM 17 locus were studied and haplotypes rebuilt. A clinical response was observed in 64% of the patients and biological response in 77.1% of patients. No association was found between the TNF gene and the response to infliximab. One haplotype in the ADAM 17 region was associated with a clinical response to infliximab in CD patients (adjusted P=0.045). In conclusion, our results exclude, with a reasonable power, an implication of the TNF gene in the response to infliximab in Crohn's disease, but reveal a potential role of the ADAM 17 gene in this response.

Departments of aHuman Genetics

bGastroenterology (CHU Liège)

cFactorial and Molecular Genetics, Centre for Biomedical Integrated Genoproteomics, University of Liège, Liège

dDepartment of Gastroenterology, UZ Gasthuisberg, Leuven

eDepartment of Gastroenterology UZ Gent, Gent

fDepartment of Gastroenterology, Erasme University Hospital, Bruxelles, Belgium

Correspondence and requests for reprints to V. Dideberg, Centre de Génétique Humaine, CHU Sart-Tilman, B35, University of Liège, 4000 Liège, Belgique

Tel: +32 43 66 81 45; fax: +32 43 66 81 46; e-mail:

Sponsorship: The University Hospital of Liège (FIRS), the National Fund for Scientific Research (FNRS, Belgium) and the Fondation Léon Frédéricq.

*The two senior authors share equal responsibility.

E. Louis is a Senior Research Associate at the FNRS Belgium. E. Théâtre is a Research Fellow at the FNRS Belgium. S. Vermeire is a postdoctoral FWO fellow.

Received 2 March 2006; Accepted 10 May 2006

© 2006 Lippincott Williams & Wilkins, Inc.