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

ABSTRACT: 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).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).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.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.

SUBMITTER: Murdoch TB

PROVIDER: S-EPMC3418471 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Murdoch Travis B TB Xu Wei W Stempak Joanne M JM Landers Carol C Targan Stephan R SR Rotter Jerome I JI Silverberg Mark S MS

Inflammatory bowel diseases 20120124 9

<h4>Background</h4>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).<h4>Methods</h4>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, ...[more]

PMID: 22275320

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Project description:Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 μg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 μg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, p = .03). The HLA-DQA1*05 rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

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

Publications

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

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