Abstract
Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10–TLR1–TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10–TLR1–TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10GGGG) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio=1.89, P-value=0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10GGGG haplotype (Pc<0.0001). The interaction gain attributed to the combination of both genes was negative (IG=−2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.
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References
Abreu MT, Arditi M . Innate immunity and toll-like receptors: clinical implications of basic science research. J Pediatr 2004; 144: 421–429.
Bouma G, Strober W . The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 2003; 3: 521–533.
Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B et al. Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet 2006; 367: 668–678.
Kanneganti TD, Lamkanfi M, Nunez G . Intracellular NOD-like receptors in host defense and disease. Immunity 2007; 27: 549–559.
Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278: 8869–8872.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.
Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y et al. Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology 2002; 123: 86–91.
Riis L, Vind I, Vermeire S, Wolters F, Katsanos K, Politi P . European Collaborative Study Group on Inflammatory Bowel Disease. The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel 2007; 13: 24–32.
Brand S, Staudinger T, Schnitzler F, Pfennig S, Hofbauer K, Dambacher J 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.
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.
Török HP, Glas J, Endres I, Tonenchi L, Teshome MY, Wetzke M et al. Epistasis between Toll-like receptor-9 polymorphisms and variants in NOD2 and IL23R modulates susceptibility to Crohn's disease. Am J Gastroenterol 2009; 104: 1723–1733.
Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.
Chuang T, Ulevitch RJ . Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta 2001; 1518: 157–161.
Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 2000; 97: 13766–13771.
Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Brière F, Vlach J, Lebecque S, Trinchieri G, Bates EE . Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 2005; 174: 2942–2950.
Tantisira K, Klimecki WT, Lazarus R, Palmer LJ, Raby BA, Kwiatkowski DJ et al. Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun 2004; 5: 343–346.
Lazarus R, Raby BA, Lange C, Silverman EK, Kwiatkowski DJ, Vercelli D et al. TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am J Respir Crit Care Med 2004; 170: 594–600.
Sun J, Wiklund F, Zheng SL, Chang B, Bälter K, Li L et al. Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J Natl Cancer Inst 2005; 97: 525–532.
Zhou XX, Jia WH, Shen GP, Qin HD, Yu XJ, Chen LZ et al. Sequence variants in toll-like receptor 10 are associated with nasopharyngeal carcinoma risk. Cancer Epidemiol Biomarkers Prev 2006; 15: 862–866.
Purdue MP, Lan Q, Wang SS, Kricker A, Menashe I, Zheng TZ et al. A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma. Carcinogenesis 2009; 30: 275–281.
Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 2002; 8: 878–884.
Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ . Expression of toll like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 2002; 105: 1158–1161.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.
Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118–1125.
Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH . Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69: 138–147.
Moore JH . Computational analysis of gene-gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn 2004; 4: 795–803.
Moore JH, Wllimas SM . Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis. BioEssays 2005; 27: 637–646.
Murray PJ . Beyond peptidoglycan for Nod2. Nat Immunol 2009; 10: 1053–1054.
van Heel DA, Ghosh S, Hunt KA, Mathew CG, Forbes A, Jewell DP, Playford RJ . Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn's disease. Gut 2005; 54: 1553–1557.
Guan Y, Ranoa DR, Jiang S, Mutha SK, Li X, Baudry J, Tapping RI . Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. J Immunol 2010; 184: 5094–5103.
Satsangi J, Silverberg MS, Vermeire S, Colombel JF . The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006; 55: 749–753.
Becker T, Knapp M . Maximum-likelihood estimation of haplotype frequencies in nuclear families. Genet Epidemiol 2004; 27: 21–32.
García-Lozano JR, Torres B, Fernández O, Orozco G, Alvarez-Márquez A, García A et al. Caspase 7 influences susceptibility to rheumatoid arthritis. Rheumatology 2007; 46: 1243–1247.
Akaike H . A new look at the statistical model identification. IEEE Trans Automat Contr 1974; 19: 716–723.
Epstein MP, Satten GA . Inference on haplotype effects in case-control studies using unphased genotype data. Am J Hum Genet 2003; 73: 1316–1329.
Jakulin A, Bratko I . Analyzing attribute depedencies. In: Lavrac N, Gamberger D, Blockeel H, Todorovski L, (eds). PKDD 2003. Cavtat Croatia: Springer-Verlag, 2003, pp 229–240.
Acknowledgements
This study was supported by Consejería de Salud de la Junta de Andalucía (Exp. 0260/08), Fondo de Investigaciones Sanitarias (FIS 07/0061), Fondos FEDER and Plan Andaluz de Investigación (PAI CTS-0197). José Manuel Lucena-Soto is the recipient of a fellowship from the Instituto de Salud Carlos III (Red de Investigación en Inflamación y Enfermedades Reumáticas, RD08/0075/0013).
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Abad, C., González-Escribano, M., Diaz-Gallo, L. et al. Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2. Genes Immun 12, 635–642 (2011). https://doi.org/10.1038/gene.2011.41
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DOI: https://doi.org/10.1038/gene.2011.41
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