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

Abstract

BackgroundThe 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.MethodsUsing 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.ResultsThe 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 (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (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).ConclusionOur 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.

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…Intestinal epithelial TLR5 expression could be beneficial in the neonate host as discussed above but the subsequent down‐regulation in absorptive enterocytes might help to prevent inappropriate stimulation in the adult host. Consistently, a loss‐of‐function polymorphism in TLR5 has been shown to protect whereas a gain‐of‐function was associated with an increased risk of inflammatory bowel disease in humans . Additionally, soluble factors in breast milk such as epidermal growth factor, the local cytokine milieu and regulatory molecules such as A20 may help to avoid inappropriate innate immune stimulation during the immediate postnatal period …”

“…Consistently, a loss-offunction polymorphism in TLR5 has been shown to protect whereas a gain-of-function was associated with an increased risk of inflammatory bowel disease in humans. 43,44 Additionally, soluble factors in breast milk such as epidermal growth factor, the local cytokine milieu and regulatory molecules such as A20 may help to avoid inappropriate innate immune stimulation during the immediate postnatal period. 28,45,46 In addition to developmental factors, the innate immune system actively adapts to the situation after birth.…”

Microbiome, inflammation, epigenetic alterations, and mental diseases

“…These diseases processes are complex and involve both environmental and genetic factors. Genetic studies have shown that polymorphisms in the Toll‐like receptor (TLR), IL‐23/IL‐17, interferon gamma (IFNG), and apoptosis pathways are associated with susceptibility to CD and UC (Bank et al, ). In the IL‐23/IL‐17 pathway, IL‐23 increases the excretion of the pro‐inflammatory cytokine IL‐17, which in turn enhances the production of pro‐inflammatory mediators such as IL‐1β, IL‐6, IL‐8, and TNF‐α (Andrews et al, ).…”

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis

“…The SNPs were evaluated for genotyping errors by assessing Hardy-Weinberg equilibrium. This was performed in a control group of healthy Danish blood donors 51 as HardyWeinberg equilibrium cannot be assessed in the current highly selected study group of patients with psoriasis selected for treatment with biological therapy. The control group was genotyped by the same method at the same laboratory.…”