Polymorphism of TNF-alfa but not MDR-1 influence response to medical therapy in pediatric onset inflammatory bowel disease. (I.F. 2.102)

Aim: We investigated the contribution of variants of tumour necrosis factor (TNF)-a and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). Patients and Methods: In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms G308A and C857T of the TNF-a gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. Results: The frequency of the 308A allele of the TNF-a gene was significantly increased in both patients with CD (15%; odds ratio [OR]¼2.79; P<0.01) and patients with UC (11%; OR¼1.96; P<0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR¼2.94; P<0.01) and 19% in UC (OR¼1.86; P¼0.015) compared with 11% in healthy controls. No significant difference was found for both the C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the 308A allele had a higher frequency of surgical resection (35% vs 20%; OR¼2.1; P¼0.035) and more frequent resistance to steroids (22% vs 8%; OR¼0.29; P¼0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. Conclusions: In our pediatric cohort, the promoter 308A polymorphism of TNF-a but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection. JPGN 44:171–179, 2007. Key Words: Genotype/phenotype—Medical therapy—Azathioprine— 6-Mercaptopurine—Methotrexate—Infliximab—Corticosteroids— Mesalamine. # 2007 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition