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

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. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.MethodsUsing 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.ResultsSixteen 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) (ORCD,adj: 0.38, 95% CI: 0.21–0.67, p = 0.03; ORIBD,adj 0.43, 95% CI: 0.28–0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (ORCD,unadj 0.54, 95% CI: 0.41–0.72, p = 7*10−4; ORIBD,unadj: 0.61, 95% CI: 0.48–0.77, p = 0.001) were associated with reduced risk of CD.ConclusionThe 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.

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

“…[6][7][8] A list of all SNPs studied is presented in Supplementary Table 1a. DNA extraction (Maxwell 16 LEV Blood DNA Kit; Promega, Madison, WI, USA) was performed as described by Bank et al…”

“…5 Pharmacogenetics has been more thoroughly investigated in inflammatory bowel disease and rheumatoid arthritis, where polymorphisms in genes encoding Toll-like receptors (TLRs) and NOD-like receptors have been found to be associated with response to anti-TNF drugs. [6][7][8][9][10] Nuclear factor-κB plays a major role in controlling inflammation and is an important regulator of pathways leading to expression of cytokines in psoriasis, including IL-1β (http://www.bu.edu/nf-kb/generesources/target-genes/). Nuclear factor-κB can be activated by TLRs and NOD-like receptors.…”

The Polymorphism rs3024505 (C/T) Downstream of the <i>IL10 </i>Gene Is Associated with Crohn’s Disease in Serbian Patients with Inflammatory Bowel Disease

“…The polymorphism C-592A was also associated with CD in Canadian pediatric patients (Amre et al 2009). However, most studies failed to find any association between IL10 promoter SNPs and susceptibility to develop IBD (Klein et al 2000;Koss et al 2000;Kim et al 2003;Balding et al 2004;Cantor et al 2005;Klausz et al 2005;Celik et al 2006;Sanchez et al 2009;Andersen et al 2010;Ahirwar et al 2012;Doecke et al 2013;Bank et al 2014;LopezHernandez et al 2015). Moreover, three meta-analysis, performed so far, were not consistent either, with each one showing associations of some of the three SNPs with one form of IBD that were not replicated by others (Zhu et al 2013;Lv et al 2014;Zou et al 2014).…”

“…The subsequent GWA studies clearly associated rs3024505 with both forms of IBD, including earlyonset UC and CD (Imielinski et al 2009;Franke et al 2010;Anderson et al 2011). The replication case-control studies that followed, found the association of T allele and TT (or CT) genotype of rs3024505 SNP with UC and/or CD in Danish, Dutch, New Zealand, Australian and North Indian IBD patients (Andersen et al 2010;Festen et al 2010;Juyal et al 2011;Doecke et al 2013;Bank et al 2014), with the exception for two studies that found no association with CD in Danish and Canadian pediatric cohorts (Amre et al 2009;Bank et al 2014). The only meta-analysis done so far, that included data from just 2 publications with 6 populations of UC patients, also associated rs3024505 with UC (Doecke et al 2013).…”

Autoimmune Thyroid Diseases Concomitant with Crohn’s Disease and Ulcerative Colitis

“…The role of non-HLA genes such as PTPN22, CTLA4, and CD40 in GD patients has been extensively investigated [11]. Although some studies reported that PTPN22 does not influence the risk of IBD, including CD [12], other studies reported that PTPN22 may influence the risk of developing CD [13,14]. Moreover, some studies reported that CTLA4 may also influence the risk of developing CD [15,16].…”