INFLAMMATORY BOWEL DISEASE

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

D Franchimont^1,*, S Vermeire^2,*, H El Housni³, M Pierik², K Van Steen⁴, T Gustot¹, E Quertinmont¹, M Abramowicz³, A Van Gossum¹, J Devière¹, P Rutgeerts²

¹ Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
² Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
³ Department of Genetics and IRIBHM, Erasme University Hospital, ULB, Brussels, Belgium
⁴ Centre for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium

Correspondence to:
Correspondence to:
Dr D Franchimont
Department of Gastroenterology, Erasme University Hospital, 808, Lennik St, 1070 Brussels, Belgium; Denis.Franchimont{at}ulb.ac.be

Background and aims: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn’s disease (CD) and/or ulcerative colitis (UC).

Methods: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios.

Results: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28–4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24–4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07–3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately.

Conclusion: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.

Abbreviations: PRR, pattern recognition receptor; TLR, toll-like receptor; LPS, lipopolysaccharide; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; LRR, leucine rich repeat; PGN, peptidoglycan; IEC, intestinal epithelial cell; TDT, transmission disequilibrium test; IC, indeterminate colitis; ASCA, anti-Saccharomyces cerevisiae antibody; BI, binding index; SNP, single nucleotide polymorphisms; PCR, polymerase chain reaction; OR, odds ratios; GAR, genotype absolute risk; GRR, genotype relative risk; RR, relative risk

Keywords: inflammatory bowel disease; toll-like receptor; tlr-4 Asp299gly; Crohn’s disease; ulcerative colitis; innate immunity

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Robin Spiller
Gut 2004 53: 917. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Roggenbuck, D, Hausdorf, G, Martinez-Gamboa, L, Reinhold, D, Buttner, T, Jungblut, P R, Porstmann, T, Laass, M W, Henker, J, Buning, C, Feist, E, Conrad, K (2009). Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease. Gut 58: 1620-1628 [Abstract] [Full Text]  
• DOAN, H. Q., BOWEN, K. A., JACKSON, L. A., EVERS, B. M. (2009). Toll-like Receptor 4 Activation Increases Akt Phosphorylation in Colon Cancer Cells. Anticancer Res 29: 2473-2478 [Abstract] [Full Text]  
• Ungaro, R., Fukata, M., Hsu, D., Hernandez, Y., Breglio, K., Chen, A., Xu, R., Sotolongo, J., Espana, C., Zaias, J., Elson, G., Mayer, L., Kosco-Vilbois, M., Abreu, M. T. (2009). A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G1167-G1179 [Abstract] [Full Text]  
• Horie, Y., Meguro, A., Ota, M., Kitaichi, N., Katsuyama, Y., Takemoto, Y., Namba, K., Yoshida, K., Song, Y. W., Park, K. S., Lee, E. B., Inoko, H., Mizuki, N., Ohno, S. (2009). Association of TLR4 polymorphisms with Behcet's disease in a Korean population. Rheumatology (Oxford) 48: 638-642 [Abstract] [Full Text]  
• Correa, I., Veny, M., Esteller, M., Pique, J. M., Yague, J., Panes, J., Salas, A. (2009). Defective IL-10 production in severe phenotypes of Crohn's disease. J. Leukoc. Biol. 85: 896-903 [Abstract] [Full Text]  
• Chen, H., Xu, H., Dong, J., Li, J., Ghishan, F. K. (2009). Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G775-G781 [Abstract] [Full Text]  
• Tuin, A, Poelstra, K, de Jager-Krikken, A, Bok, L, Raaben, W, Velders, M P, Dijkstra, G (2009). Role of alkaline phosphatase in colitis in man and rats. Gut 58: 379-387 [Abstract] [Full Text]  
• Shibuya, E., Meguro, A., Ota, M., Kashiwagi, K., Mabuchi, F., Iijima, H., Kawase, K., Yamamoto, T., Nakamura, M., Negi, A., Sagara, T., Nishida, T., Inatani, M., Tanihara, H., Aihara, M., Araie, M., Fukuchi, T., Abe, H., Higashide, T., Sugiyama, K., Kanamoto, T., Kiuchi, Y., Iwase, A., Ohno, S., Inoko, H., Mizuki, N. (2008). Association of Toll-like Receptor 4 Gene Polymorphisms with Normal Tension Glaucoma. IOVS 49: 4453-4457 [Abstract] [Full Text]  
• Williams, J. L., Minton, J. E., Patterson, J. A., Marchant Forde, J., Eicher, S. D. (2008). Lairage during transport of eighteen-kilogram pigs has an impact on innate immunity and commensal bacteria diversity in the intestines. J ANIM SCI 86: 1232-1244 [Abstract] [Full Text]  
• Albert, E. J., Marshall, J. S. (2008). Aging in the absence of TLR2 is associated with reduced IFN-{gamma} responses in the large intestine and increased severity of induced colitis. J. Leukoc. Biol. 83: 833-842 [Abstract] [Full Text]  
• Gribar, S. C., Anand, R. J., Sodhi, C. P., Hackam, D. J. (2008). The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J. Leukoc. Biol. 83: 493-498 [Abstract] [Full Text]  
• Heidemann, J., Ruther, C., Kebschull, M., Domschke, W., Bruwer, M., Koch, S., Kucharzik, T., Maaser, C. (2007). Expression of IL-12-related molecules in human intestinal microvascular endothelial cells is regulated by TLR3. Am. J. Physiol. Gastrointest. Liver Physiol. 293: G1315-G1324 [Abstract] [Full Text]  
• Henckaerts, L., Pierik, M., Joossens, M., Ferrante, M., Rutgeerts, P., Vermeire, S. (2007). Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut 56: 1536-1542 [Abstract] [Full Text]  
• Ferrante, M., Henckaerts, L., Joossens, M., Pierik, M., Joossens, S., Dotan, N., Norman, G. L, Altstock, R. T, Van Steen, K., Rutgeerts, P., Van Assche, G., Vermeire, S. (2007). New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 56: 1394-1403 [Abstract] [Full Text]  
• Awomoyi, A. A., Rallabhandi, P., Pollin, T. I., Lorenz, E., Sztein, M. B., Boukhvalova, M. S., Hemming, V. G., Blanco, J. C. G., Vogel, S. N. (2007). Association of TLR4 Polymorphisms with Symptomatic Respiratory Syncytial Virus Infection in High-Risk Infants and Young Children. J. Immunol. 179: 3171-3177 [Abstract] [Full Text]  
• Greenhall, J. A., Zapala, M. A., Caceres, M., Libiger, O., Barlow, C., Schork, N. J., Lockhart, D. J. (2007). Detecting genetic variation in microarray expression data. Genome Res 17: 1228-1235 [Abstract] [Full Text]  
• Heimesaat, M M, Fischer, A, Jahn, H-K, Niebergall, J, Freudenberg, M, Blaut, M, Liesenfeld, O, Schumann, R R, Gobel, U B, Bereswill, S (2007). Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli. Gut 56: 941-948 [Abstract] [Full Text]  
• Shibolet, O., Podolsky, D. K. (2007). TLRs in the Gut.IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G1469-G1473 [Abstract] [Full Text]  
• Merx, S., Neumaier, M., Wagner, H., Kirschning, C. J, Ahmad-Nejad, P. (2007). Characterization and investigation of single nucleotide polymorphisms and a novel TLR2 mutation in the human TLR2 gene. Hum Mol Genet 16: 1225-1232 [Abstract] [Full Text]  
• Huibregtse, I L, van Lent, A U, van Deventer, S J H (2007). Immunopathogenesis of IBD: insufficient suppressor function in the gut?. Gut 56: 584-592 [Full Text]  
• Korzenik, J R (2007). Is Crohn's disease due to defective immunity?. Gut 56: 2-5 [Abstract] [Full Text]  
• Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F., Veldhuyzen van Zanten, S. J. O. (2006). Differences between Tissue-Associated Intestinal Microfloras of Patients with Crohn's Disease and Ulcerative Colitis. J. Clin. Microbiol. 44: 4136-4141 [Abstract] [Full Text]  
• den Hartog, J.E., Morre, S.A., Land, J.A. (2006). Chlamydia trachomatis-associated tubal factor subfertility: immunogenetic aspects and serological screening. Hum Reprod Update 12: 719-730 [Abstract] [Full Text]  
• Lukas, M., Bortlik, M., Maratka, Z. (2006). What is the origin of ulcerative colitis? Still more questions than answers.. Postgrad. Med. J. 82: 620-625 [Abstract] [Full Text]  
• Bedford, P. A., Todorovic, V., Westcott, E. D. A., Windsor, A. C. J., English, N. R., Al-Hassi, H. O., Raju, K. S., Mills, S., Knight, S. C. (2006). Adipose tissue of human omentum is a major source of dendritic cells, which lose MHC Class II and stimulatory function in Crohn's disease. J. Leukoc. Biol. 80: 546-554 [Abstract] [Full Text]  
• Jilling, T., Simon, D., Lu, J., Meng, F. J., Li, D., Schy, R., Thomson, R. B., Soliman, A., Arditi, M., Caplan, M. S. (2006). The Roles of Bacteria and TLR4 in Rat and Murine Models of Necrotizing Enterocolitis.. J. Immunol. 177: 3273-3282 [Abstract] [Full Text]  
• Adam, R, Sturrock, R D, Gracie, J A (2006). TLR4 mutations (Asp299Gly and Thr399Ile) are not associated with ankylosing spondylitis.. Ann Rheum Dis 65: 1099-1101 [Abstract] [Full Text]  
• Rallabhandi, P., Bell, J., Boukhvalova, M. S., Medvedev, A., Lorenz, E., Arditi, M., Hemming, V. G., Blanco, J. C. G., Segal, D. M., Vogel, S. N. (2006). Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling. J. Immunol. 177: 322-332 [Abstract] [Full Text]  
• Romics, L. Jr, Szabo, G., Coffey, J. C., Wang, J. H., Redmond, H. P. (2006). The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases. Arch Surg 141: 595-601 [Abstract] [Full Text]  
• Ince, M. N., Elliott, D. E., Setiawan, T., Blum, A., Metwali, A., Wang, Y., Urban, J. F. Jr., Weinstock, J. V. (2006). Cutting Edge: Heligmosomoides polygyrus Induces TLR4 on Murine Mucosal T Cells That Produce TGF{beta} after Lipopolysaccharide Stimulation. J. Immunol. 176: 726-729 [Abstract] [Full Text]  
• Vogel, S. N., Awomoyi, A. A., Rallabhandi, P., Medvedev, A. E. (2005). Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview. Innate Immunity 11: 333-339 [Abstract]  
• Yamazaki, K., McGovern, D., Ragoussis, J., Paolucci, M., Butler, H., Jewell, D., Cardon, L., Takazoe, M., Tanaka, T., Ichimori, T., Saito, S., Sekine, A., Iida, A., Takahashi, A., Tsunoda, T., Lathrop, M., Nakamura, Y. (2005). Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum Mol Genet 14: 3499-3506 [Abstract] [Full Text]  
• Noble, C L, Nimmo, E R, Drummond, H, Smith, L, Arnott, I D R, Satsangi, J (2005). DLG5 variants do not influence susceptibility to inflammatory bowel disease in the Scottish population. Gut 54: 1416-1420 [Abstract] [Full Text]  
• Gomariz, R. P., Arranz, A., Abad, C., Torroba, M., Martinez, C., Rosignoli, F., Garcia-Gomez, M., Leceta, J., Juarranz, Y. (2005). Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP. J. Leukoc. Biol. 78: 491-502 [Abstract] [Full Text]  
• Grannemann, S., Landt, O., Breuer, S., Blomeke, B. (2005). LightTyper Assay with Locked-Nucleic-Acid-Modified Oligomers for Genotyping of the Toll-Like Receptor 4 Polymorphisms A896G and C1196T. Clin. Chem. 51: 1523-1525 [Full Text]  
• Cario, E (2005). BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2. Gut 54: 1182-1193 [Full Text]  
• Lanzarotto, F, Akbar, A, Ghosh, S (2005). Does innate immune response defect underlie inflammatory bowel disease in the Asian population?. Postgrad. Med. J. 81: 483-485 [Full Text]  
• Guo, Q S, Xia, B, Jiang, Y, Morre, S A, Cheng, L, Li, J, Crusius, J B A, Pena, A S (2005). Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad. Med. J. 81: 526-529 [Abstract] [Full Text]  
• Fukata, M., Michelsen, K. S., Eri, R., Thomas, L. S., Hu, B., Lukasek, K., Nast, C. C., Lechago, J., Xu, R., Naiki, Y., Soliman, A., Arditi, M., Abreu, M. T. (2005). Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288: G1055-G1065 [Abstract] [Full Text]  
• Wehkamp, J., Schmid, M., Fellermann, K., Stange, E. F. (2005). Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease. J. Leukoc. Biol. 77: 460-465 [Abstract] [Full Text]  
• Hofstaedter, F (2005). Granuloma formation in the different phenotypes of Crohn's disease. Gut 54: 180-181 [Full Text]  
• Pierik, M, De Hertogh, G, Vermeire, S, Van Assche, G, Van Eyken, P, Joossens, S, Claessens, G, Vlietinck, R, Rutgeerts, P, Geboes, K (2005). Epithelioid granulomas, pattern recognition receptors, and phenotypes of Crohn's disease. Gut 54: 223-227 [Abstract] [Full Text]  

eLetters:

Read all eLetters

The toll like receptor-4 gene in IBD: further evidence for genetic heterogeneity in Europe

Ian DR Arnott, et al.

Gut Online, 11 Aug 2004 [Full text]

Reply to Franchimont et al

Servaas A Morré, et al.

Gut Online, 16 Sep 2004 [Full text]

Reply:

Denis Franchimont, et al.

Gut Online, 2 Sep 2004 [Full text]