title: Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease.
abstract: OBJECTIVE
  The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies.
  
  
  METHODS
  179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured.
  
  
  RESULTS
  Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups.
  
  
  CONCLUSIONS
  Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse.
authors: Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, , Alicante, Spain.
authors: Ana
authors: A
authors: Gutiérrez
authors: Michael
authors: M
authors: Scharl
authors: Laura
authors: L
authors: Sempere
authors: Ernst
authors: E
authors: Holler
authors: Pedro
authors: P
authors: Zapater
authors: Isabel
authors: I
authors: Almenta
authors: José M
authors: JM
authors: González-Navajas
authors: José
authors: J
authors: Such
authors: Reiner
authors: R
authors: Wiest
authors: Gerhard
authors: G
authors: Rogler
authors: Rubén
authors: R
authors: Francés
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000097:blood / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000627:therapeutic use; D000071183:Autophagy-Related Proteins; D018988:Bacterial Translocation / Q000502:physiology*; D001691:Biological Therapy / Q000379:methods*; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000188:drug therapy* / Q000382:microbiology; D004269:DNA, Bacterial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010446:Peptide Fragments / Q000097:blood; D012008:Recurrence; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: C518959:ATG16L1 protein, human; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D004269:DNA, Bacterial; D053762:Interleukin-12 Subunit p40; D053473:Nod2 Signaling Adaptor Protein; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C069261:interferon gamma (1-39); D007371:Interferon-gamma; D000069285:Infliximab; D000068879:Adalimumab
keywords: Bacterial Translocation; Crohn'S Disease; Ibd - Genetics; Immune Response; Infliximab