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

Clinica Pediatrica Università La Sapienzá, Roma, Italy.
Journal of pediatric gastroenterology and nutrition (Impact Factor: 2.63). 03/2007; 44(2):171-9. DOI: 10.1097/MPG.0b013e31802c41f3
Source: PubMed

ABSTRACT We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha 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).
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-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy.
The frequency of the -308A allele of the TNF-alpha 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.
In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha 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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    • "Other genetic variants that impact disease behavior include an SNP in IRGM (rs4958847), which was significantly associated with frequency of surgery in a study of 66 patients with ileocecal CD, and a negative association was found between ileal disease and TLR1 S602I.76 Genetic variants may also impact the response to certain immune therapies; polymorphisms in multidrug resistant 1, TNF, and migration inhibitory factor genes have all been associated with sensitivity to corticosteroid,77,78 while variants in apoptosis genes have been used to predict the response to infliximab therapy.79 The identification of genetic variants could be an important tool in predicting disease behavior and responsiveness of certain patients to specific treatments; however, this may be complicated by the major role that other factors, such as the environment, plays in CD pathogenesis. "
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    • "Single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes have been identified, however functional data pertaining to these polymorphisms in scarce. Nonetheless, the putative role of these polymorphisms in disease susceptibility has been examined in genetic association studies of various inflammatory disorders, including Crohn's disease [10-13], ulcerative colitis [10,11,14], systemic lupus erythematosus [15-17] and rheumatoid arthritis [18,19]. More recently, given that cancer progression is preceded by a long period of subclinical inflammation [20-22], the genetic polymorphisms of TNF-α, TNFRSF1A and TNFRSF1B have been examined in terms of susceptibility to various cancers [23-28]. "
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