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PLoS One. 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.

Author information

1
Medical Department, Viborg Regional Hospital, Viborg, Denmark; Biomedicine, University of Aarhus, Aarhus, Denmark.
2
Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
3
Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
4
Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.
5
Medical Department, Køge Hospital, Køge, Denmark.
6
Medical Department, Hillerød Hospital, Hillerød, Denmark.
7
Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark.
8
Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark.
9
Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.
10
Medical Department V, Aarhus University Hospital, Aarhus, Denmark.
11
Medical Department, Slagelse Hospital, Slagelse, Denmark.
12
Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
13
Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.
14
International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.
15
Section of Biostatistics, Department of Public health, Aarhus University, Aarhus, Denmark.
16
Biomedicine, University of Aarhus, Aarhus, Denmark.
17
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
18
National Research Centre for the Working Environment, Copenhagen, Denmark.
19
Medical Department, Viborg Regional Hospital, Viborg, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Organ Centre, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark; OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.

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.

PMID:
24971461
PMCID:
PMC4074037
DOI:
10.1371/journal.pone.0098815
[Indexed for MEDLINE]
Free PMC Article

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