Pattern recognition receptor and autophagy gene variants are associated with development of antimicrobial antibodies in Crohn's disease

  • Murdoch T
  • Xu W
  • Stempak J
 et al. 
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BACKGROUND: We sought to investigate whether variants in genes involved in bacterial sensing and autophagy (NOD2, TLR5, IRGM, ATG16L1) and the interleukin-23 signaling pathway (IL12B, IL23R, STAT3) were associated with development of antimicrobial antibodies in patients with Crohn's disease (CD). METHODS: A cohort of 616 CD patients from a tertiary referral hospital (Mount Sinai Hospital, Toronto) was evaluated. DNA was tested for three CD-associated NOD2 variants (3020insC, G908R, R702W), variants in IRGM, ATG16L1, IL12B, IL23R, STAT3, and a TLR5-stop mutation. Serum was analyzed by enzyme-linked immunosorbent assay (ELISA) for anti-Saccharomyces cerevisiae (ASCA) IgG and IgA, anti-outer membrane porin C (anti-ompC), anti-Cbir1 flagellin, and anti-Pseudomonas fluorescens (anti-I2). RESULTS: NOD2 3020insC was associated with cumulative seroreactivity by quartile sum (P = 0.003) and number of positive antibodies (P = 0.02). NOD2 G908R was also associated with quartile sum (P = 0.05). Increased ASCA seropositivity was associated with NOD2 3020insC (odds ratio [OR] = 1.9, P = 0.02) and G908R (OR = 1.8, P = 0.05), and ATG16L1 T300A (OR = 1.4, P = 0.01) variants; ASCA-positive patients had an increased cumulative number of NOD2 3020insC and ATG16L1 T300A variants (P = 0.007). TLR5-stop mutation abrogated development of anti-flagellin in a dominant-negative fashion (OR = 0.5, P = 0.009). The IRGM CD risk variant was associated with increased anti-flagellin seropositivity (OR = 1.5, P = 0.03). IL12B, IL23R, and STAT3 variants did not contribute to development of antimicrobial antibodies. CONCLUSIONS: Variants in innate immune genes involved in pattern recognition and autophagy but not the interleukin-23 signaling pathway influence antimicrobial seroreactivity in CD. In particular, the additive effect of NOD2 3020insC and ATG16L1 T300A suggests a role for autophagy in development of ASCA.

Author-supplied keywords

  • *Autophagy
  • Adolescent
  • Adult
  • Antibodies, Bacterial/*blood
  • Antibodies, Fungal/blood
  • Antigens, Bacterial/immunology
  • Carrier Proteins/genetics
  • Child
  • Child, Preschool
  • Crohn Disease/*genetics/*microbiology/pathology
  • DNA/genetics
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • GTP-Binding Proteins/genetics
  • Humans
  • Interleukin-12 Subunit p40/genetics
  • Male
  • Middle Aged
  • Mutation/*genetics
  • Nod2 Signaling Adaptor Protein/genetics
  • Polymerase Chain Reaction
  • Polymorphism, Genetic/*genetics
  • Receptors, Interleukin/genetics
  • Receptors, Pattern Recognition/*genetics
  • STAT3 Transcription Factor/genetics
  • Saccharomyces cerevisiae/immunology
  • Tertiary Care Centers
  • Toll-Like Receptor 5/genetics
  • Young Adult

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  • T B Murdoch

  • W Xu

  • J M Stempak

  • C Landers

  • S R Targan

  • J I Rotter

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