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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 60

Record: found
Abstract: found
Article: not found

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.

Andre Franke, Tobias Balschun, Tom H. Karlsen … (2008)

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 x 10(-12); OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

0 comments Cited 139 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme.

T Bekaert, T Bekaert, Anhtung Chau … (2008)

Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kappaB (NF-kappaB). TLR, IL-1R and TNF-R signaling to NF-kappaB converge on a common IkappaB kinase complex that phosphorylates the NF-kappaB inhibitory protein IkappaBalpha. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kappaB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.

0 comments Cited 131 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Inflammatory Bowel Disease

Siavosh Nasseri-Moghaddam, Peter Moses (2012)

Inflammatory bowel disease (IBD) is the term used for a group of diseases with yet unknown etiology, prevalence of which is increasing almost everywhere in the world. The disease was almost non-existent four decades ago in the east, including the middle-east, while now a days it is seen more and more. In addition to the increasing prevalence, our knowledge about its pathogenesis, clinical course, diagnosis, and treatment has changed dramatically over the past couple of decades. This has changed our concept of this group of diseases, their diagnosis, treatment, and treatment goals. Considering the vast literature on the subject, it is timely to review major topics in IBD with a look on the regional progress and knowledge as well. This essay is aimed to cover this task.

0 comments Cited 110 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Markus M. Heimesaat: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 27 June 2014

Volume: 9

Issue: 6

Electronic Location Identifier: e98815

Affiliations

[1 ]Medical Department, Viborg Regional Hospital, Viborg, Denmark

[2 ]Biomedicine, University of Aarhus, Aarhus, Denmark

[3 ]Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark

[4 ]Department of Gastroenterology, Herlev Hospital, Herlev, Denmark

[5 ]Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark

[6 ]Medical Department, Køge Hospital, Køge, Denmark

[7 ]Medical Department, Hillerød Hospital, Hillerød, Denmark

[8 ]Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark

[9 ]Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark

[10 ]Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark

[11 ]Medical Department V, Aarhus University Hospital, Aarhus, Denmark

[12 ]Medical Department, Slagelse Hospital, Slagelse, Denmark

[13 ]Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark

[14 ]Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark

[15 ]International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark

[16 ]Section of Biostatistics, Department of Public health, Aarhus University, Aarhus, Denmark

[17 ]Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

[18 ]Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark

[19 ]Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark

[20 ]National Research Centre for the Working Environment, Copenhagen, Denmark

[21 ]Organ Centre, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark

[22 ]OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark

Charité, Campus Benjamin Franklin, Germany

Author notes

* E-mail: stb@ 123456mb.au.dk

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.

Conceived and designed the experiments: SB PSA MF BAN JS UV VA. Performed the experiments: SB JB NP S. Roug JG SYT JBB S. Rashid BKR SA TBO HJH MKT VØT. Analyzed the data: SB PSA MF BAN JS UV VA. Contributed reagents/materials/analysis tools: SB JB NP S. Roug JG SYT JBB S. Rashid BKR SA TBO HJH MKT VØT MF. Wrote the paper: SB PSA UV VA. Drafting the article or revising it critically: SB PSA JB NP S. Roug JG SYT JBB S. Rashid BKR SA TBO HJH MKT VØT MF BAN JS UV VA. Final approval of the version to be published: SB PSA JB NP S. Roug JG SYT JBB S. Rashid BKR SA TBO HJH MKT VØT MF BAN JS UV VA.

Article

Publisher ID: PONE-D-14-09659

DOI: 10.1371/journal.pone.0098815

PMC ID: 4074037

PubMed ID: 24971461

SO-VID: 382243a8-e0f4-4c5b-80c9-0bb020d6e90c

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 4 March 2014

Date accepted : 7 May 2014

Page count

Pages: 10

Funding

The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and University of Aarhus (PhD grant). VA receives compensation as a consultant for Merck & Co., Inc. (MSD) and Janssen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

Read this article at

Abstract

Background

Methods

Results

Conclusion

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 60

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.

TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme.

Inflammatory Bowel Disease

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 256

Cited by 45

Most referenced authors 1,366