title: Polymorphisms of tumor necrosis factor-alpha but not MDR1 influence response to medical therapy in pediatric-onset inflammatory bowel disease.
abstract: OBJECTIVE
  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).
  
  
  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-alpha 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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinica Pediatrica Università La Sapienzá, Roma, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
authors.forename: Orazio
authors.initials: O
authors.lastname: Palmieri
authors.forename: Roberto Berni
authors.initials: RB
authors.lastname: Canani
authors.forename: Renata
authors.initials: R
authors.lastname: D'Incà
authors.forename: Graziella
authors.initials: G
authors.lastname: Guariso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vieni
authors.forename: Domenica
authors.initials: D
authors.lastname: De Venuto
authors.forename: Gabriele
authors.initials: G
authors.lastname: Riegler
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: De'Angelis
authors.forename: Danila
authors.initials: D
authors.lastname: Guagnozzi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bascietto
authors.forename: Erasmo
authors.initials: E
authors.lastname: Miele
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Valvano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bossa
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha