The TNF/ADAM 17 system: implication of an ADAM 17 haplotype in the clinical response to infliximab in Crohn's disease.
Infliximab, a chimeric anti-tumour necrosis factor (TNF)-alpha 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-alpha 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-alpha 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.
Dideberg
Vinciane
V
Department of Human Genetics, Centre for Biomedical Integrated Genoproteomics, University of Liège, Liège, Belgium. vinciane.dideberg@chu.ulg.ac.be
Théâtre
Emilie
E
Farnir
Frédéric
F
Vermeire
Séverine
S
Rutgeerts
Paul
P
De Vos
Martine
M
Belaiche
Jacques
J
Franchimont
Denis
D
Van Gossum
André
A
Louis
Edouard
E
Bours
Vincent
V
D051722:ADAM Proteins / Q000235:genetics*; D000072198:ADAM17 Protein; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001483:Base Sequence; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics; D017931:DNA Primers; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006239:Haplotypes; D006801:Humans; D000069285:Infliximab; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human