Polymorphisms of Tumor Necrosis Factor-α but Not MDR1 Influence Response to Medical Therapy in Pediatric-Onset Inflammatory Bowel Disease

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Abstract

Aim:

We investigated the contribution of variants of tumour necrosis factor (TNF)-α 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-α 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-α gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) 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%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression.

Conclusions:

In our pediatric cohort, the promoter −308A polymorphism of TNF-α 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.

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