Polymorphisms in the Toll-like receptor and the IL-23/IL-17 pathways were associated with susceptibility to inflammatory bowel disease in a Danish cohort

BACKGROUND:The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC. METHODS:Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. RESULTS:The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (pC (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59-6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64-5.32, p = 0.005). CONCLUSION:Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC

Diagnosis and management of iatrogenic endoscopic perforations: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement - Update 2020

ESGE recommends that each center implements a written policy regarding the management of iatrogenic perforations, including the definition of procedures that carry a higher risk of this complication. This policy should be shared with the radiologists and surgeons at each center. 2 ESGE recommends that in the case of an endoscopically identified perforation, the endoscopist reports its size and location, with an image, and statement of the endoscopic treatment that has been applied. 3 ESGE recommends that symptoms or signs suggestive of iatrogenic perforation after an endoscopic procedure should be rapidly and carefully evaluated and documented with a computed tomography (CT) scan. 4 ESGE recommends that endoscopic closure should be considered depending on the type of the iatrogenic perforation, its size, and the endoscopist expertise available at the center. Switch to carbon dioxide (CO2) endoscopic insufflation, diversion of digestive luminal content, and decompression of tension pneumoperitoneum or pneumothorax should also be performed. 5 ESGE recommends that after endoscopic closure of an iatrogenic perforation, further management should be based on the estimated success of the endoscopic closure and on the general clinical condition of the patient. In the case of no or failed endoscopic closure of an iatrogenic perforation, and in patients whose clinical condition is deteriorating, hospitalization and surgical consultation are recommended

Polymorphisms in the Inflammatory Pathway Genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG Are Associated with Susceptibility of Inflammatory Bowel Disease in a Danish Cohort

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p ≤ 0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (OR(CD,adj): 0.38, 95% CI: 0.21-0.67, p = 0.03; OR(IBD,adj) 0.43, 95% CI: 0.28-0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (OR(CD,unadj) 0.54, 95% CI: 0.41-0.72, p = 7*10-4; OR(IBD,unadj): 0.61, 95% CI: 0.48-0.77, p = 0.001) were associated with reduced risk of CD.The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals

The biologic effect of the studied single nucleotide polymorphism (SNP) and odds ratios (OR) for polymorphisms which have been shown to be associated with risk of Crohn's disease (CD), ulcerative colitis (UC) or inflammatory bowel disease (IBD) in previous studies and in this study.

A<p>Crude (unadjusted).</p>B<p>Adjusted for age, gender and smoking status.</p>C<p>Function examined by flow cytometry.</p>D<p>Function examined by luciferase reporter assay.</p>E<p>Function examined by enzyme-linked immunosorbent assay (ELISA).</p>F<p>Function examined by reverse transcriptase PCR (RT-PCR).</p>G<p>Function examined by electrophoretic mobility shift assay (EMSA).</p><p>ND: not determined.</p

Description of the study participants.

<p>Description of the study participants.</p

Sixteen functional single nucleotide polymorphisms (SNPs) in 13 genes involved in regulation of inflammation were found to be associated with susceptability of severe Crohn's disease (CD), ulcerative colitis (UC) or inflammatory bowel diseases (IBD).

<p>Eleven of the SNPs have not previously been reported as susceptability polymorphisms of CD, UC or IBD (<i>TLR2</i> (rs4696480 and rs1816702), <i>TLR4</i> (rs1554973 and rs12377632), <i>TLR9</i> (rs187084 and rs352139), <i>LY96</i> (rs11465996), <i>NFKBIA</i> (rs696), <i>TNFRSF1A</i> (rs4149570), <i>IL6R</i> (rs4537545) and <i>PTPN22</i> (rs2476601)).</p