PDF
ePub
Citation
Print
Abstract
Background/Aims
Toll-like receptors (TLRs) serve as pattern recognition receptors that recognize specific molecular patterns of pathogens and can mediate the production of proinflammatory cytokines. Recently, TLRs have been identified as susceptibility genes for Crohn's disease (CD) in several studies from Western populations. We investigated the association of genetic variations in TLR4 and TLR9 with CD in Korean population.
Methods
In 380 CD cases and 380 healthy controls, we performed genotyping for TLR4 Asp299Gly (rs4986790) and Thr399Ile (rs4986791). The genetic variations in the TLR9 -1237T/C (rs5743836) were also examined.
REFERENCES
1. Rutgeerts P, Goboes K, Peeters M, et al. Effect of faecal stream diversion on recurrence of Crohn's disease in the neo-terminal ileum. Lancet. 1991; 338:771–774.
2. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004; 126:1620–1633.
3. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002; 347:417–429.
4. Duchmann R, May E, Heike M, et al. T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut. 1999; 44:812–818.
5. Landers CJ, Cohavy O, Misra R, et al. Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto-and microbial antigens. Gastroenterology. 2002; 123:689–699.
6. Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994; 180:2359–2364.
7. Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998; 66:5224–5241.
8. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003; 278:8869–8872.
9. Inohara N, Chamaillard M, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005; 74:355–383.
10. Lee KM. Innate and adaptive immunity in IBD. Korean J Gastroenterol. 2007; 50:S3–S13.
11. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001; 411:599–603.
12. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001; 411:603–606.
13. Hampe J, Cuthbert A, Croucher PJ, et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet. 2001; 357:1925–1928.
14. Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002; 122:867–874.
15. Vermeire S, Wild G, Kocher K, et al. CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet. 2002; 71:74–83.
16. Helio T, Halme L, Lappalainen M, et al. CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease. Gut. 2003; 52:558–562.
17. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001; 1:135–145.
18. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000; 68:7010–7017.
19. Hausmann M, Kiessling S, Mestermann S, et al. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology. 2002; 122:1987–2000.
20. Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000; 25:187–191.
21. Kiechl S, Lorenz E, Reindl M, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002; 347:185–192.
22. Lorenz E, Mira JP, Frees KL, et al. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002; 162:1028–1032.
23. Franchimont D, Vermeire S, El Housni H, et al. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut. 2004; 53:987–992.
24. Agnese DM, Calvano JE, Hahm SJ, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002; 186:1522–1525.
25. Török HP, Glas J, Tonenchi L, Mussack T, Folwaczny C. Polymorphisms of the lipopolysaccharidesignaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol. 2004; 112:85–91.
26. Török HP, Glas J, Tonenchi L, Bruennler G, Folwaczny M, Folwaczny C. Crohn's disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology. 2004; 127:365–366.
27. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J Gastroenterol Hepatol. 2007; 22:1760–1766.
28. Okayama N, Fujimura K, Suehiro Y, et al. Simple genotype analysis of the Asp299Gly polymorphism of the Toll-like receptor-4 gene that is associated with lipopolysaccharide hyporesponsiveness. J Clin Lab Anal. 2002; 16:56–58.
29. Guo QS, Xia B, Jiang Y, et al. Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad Med J. 2005; 81:526–529.
30. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19(suppl A):S5–S36.
31. Yang SK, Lim J, Chang HS, et al. Association of TNFSF15 with Crohn's disease in Koreans. Am J Gastroenterol. 2008; 103:1437–1442.
32. Arnott ID, Nimmo ER, Drummond HE, et al. NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe? Genes Immun. 2004; 5:417–425.
33. Braat H, Stokkers P, Hommes T, et al. Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. J Mol Med. 2005; 83:601–609.
34. Oostenbrug LE, Drenth JP, de Jong DJ, et al. Association between Toll-like receptor 4 and inflammatory bowel disease. Inflamm Bowel Dis. 2005; 11:567–575.
35. Ouburg S, Mallant-Hent R, Crusius JB, et al. The toll-like receptor 4 (TLR4) Asp299Gly polymorphism is associated with colonic localisation of Crohn's disease without a major role for the Saccharomyces cerevisiae mannan-LBP-CD14TLR4 pathway. Gut. 2005; 54:439–440.
36. Gazouli M, Mantzaris G, Kotsinas A, et al. Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population. World J Gastroenterol. 2005; 11:681–685.
37. Brand S, Staudinger T, Schnitzler F, et al. The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease. Inflamm Bowel Dis. 2005; 11:645–652.
38. Lakatos PL, Lakatos L, Szalay F, et al. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. World J Gastroenterol. 2005; 11:1489–495.
39. Fries W, Renda MC, Lo Presti MA, et al. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. Am J Gastroenterol. 2005; 100:2730–2736.
40. Browning BL, Huebner C, Petermann I, et al. Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with metaanalysis shows strong evidence for association. Am J Gastroenterol. 2007; 102:2504–2512.
41. Hur JW, Shin HD, Park BL, Kim LH, Kim SY, Bae SC. Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus. Tissue Antigens. 2005; 65:266–270.
42. Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology. 2002; 123:679–688.
43. Radlmayr M, Török HP, Martin K, Folwaczny C. The c-insertion mutation of the NOD2 gene is associated with fistulizing and fibrostenotic phenotypes in Crohn's disease. Gastroenterology. 2002; 122:2091–2092.
44. Croucher PJ, Mascheretti S, Hampe J, et al. Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet. 2003; 11:6–16.
45. Lee GH, Kim CG, Kim JS, Jung HC, Song IS. Frequency analysis of NOD2 gene mutations in Korean patients with Crohn's disease. Korean J Gastroenterol. 2005; 45:162–168.
46. Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. J Hum Genet. 2002; 47:469–472.
47. Inoue N, Tamura K, Kinouchi Y, et al. Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology. 2002; 123:86–91.
48. Leong RW, Armuzzi A, Ahmad T, et al. NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population. Aliment Pharmacol Ther. 2003; 17:1465–1470.
49. Rioux JD, Silverberg MS, Daly MJ, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet. 2000; 66:1863–1870.
50. Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004; 36:471–475.
51. Stoll M, Corneliussen B, Costello CM, et al. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet. 2004; 36:476–480.
52. Yamazaki K, Takazoe M, Tanaka T, et al. Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease. J Hum Genet. 2004; 49:664–668.
53. Yamazaki K, McGovern D, Ragoussis J, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum Mol Genet. 2005; 14:3499–3506.
54. The Wellcome Trust Case Control Consortium. Genomewide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature. 2007; 447:661–678.
55. Tremelling M, Berzuini C, Massey D, et al. Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population. Inflamm Bowel Dis. 2008; 14:733–737.
56. Duerr RH, Taylor KD, Brant SR, et al. A genomewide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314:1461–1463.
57. Hampe J, Franke A, Rosenstiel P, et al. A genomewide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007; 39:207–211.
58. Yamazaki K, Onouchi Y, Takazoe M, et al. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. J Hum Genet. 2007; 52:575–583.
59. Yang SK, Park M, Lim J, et al. Contribution of IL23R but not ATG16L1 to Crohn's disease susceptibility in Koreans. Inflamm Bowel Dis. 2009; 15:1385–1390.
60. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong District, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis. 2008; 14:542–549.
61. Yao T, Matsui T, Hiwatashi N. Crohn's disease in Japan: diagnostic criteria and epidemiology. Dis Colon Rectum. 2000; 43:S85–S93.
62. Moum B, Vatn MH, Ekbom A, et al. Incidence of Crohn's disease in four counties in southeastern Norway, 1990-93. A prospective population-based study. The Inflammatory Bowel SouthEastern Norway (IBSEN) Study Group of Gastroenterologists. Scand J Gastroenterol. 1996; 31:355–361.
63. Vind I, Riis L, Jess T, et al. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database. Am J Gastroenterol. 2006; 101:1274–1282.
64. Bjornsson S, Johannsson JH. Inflammatory bowel disease in Iceland, 1990-1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol. 2000; 12:31–38.
65. Crawford DC, Akey DT, Nickerson DA. The patterns of natural variation in human genes. Annu Rev Genomics Hum Genet. 2005; 6:287–312.
Table 1.
Clinical Characteristics of the Study Subjects
| Patients (n=380) n (%) | Control (n=380) n (%) | p-value∗ | |
|---|---|---|---|
| Male | 238 (62.6) | 214 (56.3) | 0.089 |
| Mean age at | 27.2±7.7 | 36.6±13.8 | ＜0.001 |
| sampling (yr) | |||
| Mean age at | 23.5±7.3 | ||
| diagnosis (yr) | |||
| Mean duration of | 45.0±42.0 | ||
| disease at sampling (mo) | |||
| Age group at diagnosis | |||
| ≤16 years | 53 (13.9) | 0 (0) | |
| 17-40 years | 318 (83.7) | 233 (61.3) | |
| ＞40 years | 9 (2.4) | 147 (38.7) | |
| Localization | |||
| Ileum | 79 (20.8) | ||
| Colon | 31 (8.2) | ||
| Ileocolon | 270 (71.1) | ||
| Behavior | |||
| Inflammatory | 166 (43.7) | ||
| Stricturing | 112 (29.5) | ||
| Penetrating | 102 (26.8) | ||
| Perianal fistula | 209 (55.0) |
Table 2.
Genotype and Allele Distribution for the TLR4 Asp299Gly
| TLR4 Asp299Gly | Crohn's disease (n=360) | Control (n=337) | p-value∗ | |
|---|---|---|---|---|
| Genotype, n (%) | AA | 360 (100%) | 336 (99.7%) | |
| AG | 0 (0%) | 0 (0%) | 0.484 | |
| GG | 0 (0%) | 1 (0.3%) | ||
| Allele (%) | A | 100% | 99.7% | 0.234 |
| G | 0% | 0.3% |
Table 3.
Genotype and Allele Distribution for the TLR9 -1237 C/T
| TLR9 -1237 C/T | Crohn's disease (n=366) | Control (n=351) | p-value∗ | |
|---|---|---|---|---|
| Genotype, n (%) | TT | 366 (100%) | 350 (99.7%) | |
| TC | 0 (0%) | 1 (0.3%) | 0.490 | |
| CC | 0 (0%) | 0 (0%) | ||
| Allele (%) | T | 100% | 99.9% | 0.490 |
| C | 0% | 0.1% |
XML Download