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. 2014 Jun 27;9(6):e98815.
doi: 10.1371/journal.pone.0098815. eCollection 2014.

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

Steffen Bank  1 , Paal Skytt Andersen  2 , Johan Burisch  3 , Natalia Pedersen  3 , Stine Roug  4 , Julie Galsgaard  5 , Stine Ydegaard Turino  6 , Jacob Broder Brodersen  7 , Shaista Rashid  8 , Britt Kaiser Rasmussen  9 , Sara Avlund  10 , Thomas Bastholm Olesen  11 , Hans Jürgen Hoffmann  12 , Marianne Kragh Thomsen  13 , Vibeke Ostergaard Thomsen  14 , Morten Frydenberg  15 , Bjørn Andersen Nexø  16 , Jacob Sode  17 , Ulla Vogel  18 , Vibeke Andersen  19
Affiliations

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

Steffen Bank et al. PLoS One. .

Abstract

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. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.

Methods: 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.

Results: 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.

Conclusion: 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.

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Conflict of interest statement

Competing Interests: PSA, VØT and JS have affiliation to Statens Serum Institut. Statens Serum Institut is not a commercial company. It is a public enterprise under the Danish Ministry of Health (please see http://www.ssi.dk/English/Service/AboutSSI.aspx). This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. 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).
Eleven of the SNPs have not previously been reported as susceptability polymorphisms of CD, UC or IBD (TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084 and rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFRSF1A (rs4149570), IL6R (rs4537545) and PTPN22 (rs2476601)).
See this image and copyright information in PMC

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