title: 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: 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.
  
  
  CONCLUSIONS
  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.
authors: Medical Department, Viborg Regional Hospital, Viborg, Denmark; Biomedicine, University of Aarhus, Aarhus, Denmark.
authors: Steffen
authors: S
authors: Bank
authors: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors: Paal
authors: P
authors: Skytt Andersen
authors: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors: Johan
authors: J
authors: Burisch
authors: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors: Natalia
authors: N
authors: Pedersen
authors: Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.
authors: Stine
authors: S
authors: Roug
authors: Medical Department, Køge Hospital, Køge, Denmark.
authors: Julie
authors: J
authors: Galsgaard
authors: Medical Department, Hillerød Hospital, Hillerød, Denmark.
authors: Stine
authors: S
authors: Ydegaard Turino
authors: Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark.
authors: Jacob Broder
authors: JB
authors: Brodersen
authors: Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark.
authors: Shaista
authors: S
authors: Rashid
authors: Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.
authors: Britt
authors: B
authors: Kaiser Rasmussen
authors: Medical Department V, Aarhus University Hospital, Aarhus, Denmark.
authors: Sara
authors: S
authors: Avlund
authors: Medical Department, Slagelse Hospital, Slagelse, Denmark.
authors: Thomas
authors: T
authors: Bastholm Olesen
authors: Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors: Hans
authors: H
authors: Jürgen Hoffmann
authors: Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Marianne
authors: M
authors: Kragh Thomsen
authors: International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.
authors: Vibeke
authors: V
authors: Ostergaard Thomsen
authors: Section of Biostatistics, Department of Public health, Aarhus University, Aarhus, Denmark.
authors: Morten
authors: M
authors: Frydenberg
authors: Biomedicine, University of Aarhus, Aarhus, Denmark.
authors: Bjørn
authors: B
authors: Andersen Nexø
authors: 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.
authors: Jacob
authors: J
authors: Sode
authors: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors: Ulla
authors: U
authors: Vogel
authors: 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.
authors: Vibeke
authors: V
authors: Andersen
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*
chemical_list: D007378:Interleukins; D016328:NF-kappa B; D047495:PPAR gamma; D051193:Toll-Like Receptors; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22