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

被引：107

作者：

Bank, Steffen ^{[1
,2
]}

Andersen, Paal Skytt ^{[3
]}

Burisch, Johan ^{[4
]}

Pedersen, Natalia ^{[4
]}

Roug, Stine ^{[5
]}

Galsgaard, Julie ^{[6
]}

Turino, Stine Ydegaard ^{[7
]}

Brodersen, Jacob Broder ^{[8
]}

Rashid, Shaista ^{[9
]}

Rasmussen, Britt Kaiser ^{[10
]}

Avlund, Sara ^{[11
]}

Olesen, Thomas Bastholm ^{[12
]}

Hoffmann, Hans Jurgen ^{[13
]}

Thomsen, Marianne Kragh ^{[14
]}

Thomsen, Vibeke Ostergaard ^{[15
]}

Frydenberg, Morten ^{[16
]}

Nexo, Bjorn Andersen ^{[2
,17
]}

Sode, Jacob ^{[3
,18
]}

Vogel, Ulla ^{[19
]}

Andersen, Vibeke ^{[1
,17
,20
,21
]}

机构：

[1] Viborg Reg Hosp, Dept Med, Viborg, Denmark

[2] Univ Aarhus, Aarhus, Denmark

[3] Statens Serum Inst, DK-2300 Copenhagen, Denmark

[4] Herlev Hosp, Dept Gastroenterol, DK-2730 Herlev, Denmark

[5] Hvidovre Univ Hosp, Dept Gastroenterol, Hvidovre, Denmark

[6] Koge Hosp, Dept Med, Koge, Denmark

[7] Hillerod Hosp, Dept Med, Hillerod, Denmark

[8] Sydvestjysk Hosp, Dept Med, Esbjerg, Denmark

[9] Bispebjerg Hosp, Dept Med, Bispebjerg, Denmark

[10] Nykobing Falster Hosp, Dept Med, Nykobing, Denmark

[11] Aarhus Univ Hosp, Dept Med 5, DK-8000 Aarhus, Denmark

[12] Slagelse Hosp, Dept Med, Slagelse, Denmark

[13] Aarhus Univ Hosp, Inst Clin Med, Dept Resp Dis B, DK-8000 Aarhus, Denmark

[14] Aarhus Univ Hosp, Dept Clin Microbiol, DK-8000 Aarhus, Denmark

[15] Statens Serum Inst, Int Reference Lab Mycobacteriol, DK-2300 Copenhagen, Denmark

[16] Aarhus Univ, Dept Publ Hlth, Biostat Sect, Aarhus, Denmark

[17] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[18] Frederiksberg Univ Hosp, Dept Rheumatol, Frederiksberg, Denmark

[19] Natl Res Ctr Working Environm, Copenhagen, Denmark

[20] Hosp Southern Jutland Aabenraa, Organ Ctr, Aabenraa, Denmark

[21] Odense Univ Hosp, OPEN Odense Patient data Explorat Network, DK-5000 Odense, Denmark

来源：

PLOS ONE | 2014年 / 9卷 / 06期

关键词：

SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; TOLL-LIKE RECEPTORS; COLITIS RISK LOCI; CROHNS-DISEASE; ULCERATIVE-COLITIS; PROMOTER; EXPRESSION; GAMMA;

D O I：

10.1371/journal.pone.0098815

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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) (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. 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.

引用

页数：10

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