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23.04.2016 | Original Article

Common NOD2/CARD15 and TLR4 Polymorphisms Are Associated with Crohn’s Disease Phenotypes in Southeastern Brazilians

verfasst von: Yolanda F. M. Tolentino, Paula Peruzzi Elia, Homero Soares Fogaça, Antonio José V. Carneiro, Cyrla Zaltman, Rodrigo Moura-Neto, Ronir Raggio Luiz, Maria da Gloria C. Carvalho, Heitor S. de Souza

Erschienen in: Digestive Diseases and Sciences | Ausgabe 9/2016

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Abstract

Aim

To investigate whether variants in NOD2/CARD15 and TLR4 are associated with CD and ulcerative colitis (UC) in a genetically admixed population of Rio de Janeiro, where IBD has continued to rise.

Methods

We recruited 67 consecutive patients with CD, 61 patients with UC, and 86 healthy and ethnically matched individuals as controls. DNA was extracted from buccal brush samples and genotyped by PCR with restriction enzymes for G908R and L1007finsC NOD2/CARD15 single-nucleotide polymorphisms (SNPs) and for T399I and D299G TLR4 SNPs. Clinical data were registered for subsequent analysis with multivariate models.

Results

NOD2/CARD15 G908R and L1007finsC SNPs were found in one and three patients, respectively, with CD. NOD2/CARD15 G908R and L1007finsC SNPs were not found in any patients with UC, but were found in three and three controls, respectively. With regard to the TLR4 gene, no significant difference was detected among the groups. Overall, none of the SNPs investigated determined a differential risk for a specific diagnosis. Genotype–phenotype associations were found in only CD, where L1007finsC was associated with colonic localization; however, TLR4 T399I SNP was associated with male gender, and D299G SNP was associated with colonic involvement, chronic corticosteroid use, and the need for anti-TNF-alpha therapy.

Conclusion

Variants of NOD2/CARD15 and TLR4 do not confer susceptibility to IBD, but appear to determine CD phenotypes in this southeastern Brazilian population.

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Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8:458–466. doi:10.1038/nri2340.CrossRefPubMed

Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39:830–832. doi:10.1038/ng2061.CrossRefPubMedPubMedCentral

Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211. doi:10.1038/ng1954.CrossRefPubMed

Mathew CG. New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet. 2008;9:9–14. doi:10.1038/nrg2203.CrossRefPubMed

Jostins L, Ripke S, Weersma RK, et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124. doi:10.1038/nature11582.CrossRefPubMedPubMedCentral

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. doi:10.1038/35079107.CrossRefPubMed

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. doi:10.1038/35079114.CrossRefPubMed

Cleynen I, Gonzalez JR, Figueroa C, et al. Genetic factors conferring an increased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut. 2013;62:1556–1565. doi:10.1136/gutjnl-2011-300777.CrossRefPubMed

Strober W, Watanabe T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn’s disease. Mucosal Immunol. 2011;4:484–495. doi:10.1038/mi.2011.29.CrossRefPubMedPubMedCentral

10.

Cooney R, Baker J, Brain O, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–97. doi:10.1038/nm.2069.CrossRefPubMed

11.

Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014;14:9–23. doi:10.1038/nri3565.CrossRefPubMed

12.

Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014;13:3–10. doi:10.1016/j.autrev.2013.06.004.CrossRefPubMed

13.

Furrie E, Macfarlane S, Thomson G, et al. Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology. 2005;115:565–574. doi:10.1111/j.1365-2567.2005.02200.x.CrossRefPubMedPubMedCentral

14.

Cario E. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut. 2005;54:1182–1193. doi:10.1136/gut.2004.062794.CrossRefPubMedPubMedCentral

15.

Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004;5:800–808. doi:10.1038/ni1092.CrossRefPubMed

16.

Canto E, Moga E, Ricart E, et al. MDP-Induced selective tolerance to TLR4 ligands: impairment in NOD2 mutant Crohn’s disease patients. Inflamm Bowel Dis. 2009;15:1686–1696. doi:10.1002/ibd.21013.CrossRefPubMed

17.

Wells JM, Loonen LM, Karczewski JM. The role of innate signaling in the homeostasis of tolerance and immunity in the intestine. Int J Med Microbiol. 2010;300:41–48. doi:10.1016/j.ijmm.2009.08.008.CrossRefPubMed

18.

Vamadevan AS, Fukata M, Arnold ET, et al. Regulation of Toll-like receptor 4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis. Innate Immun. 2010;16:93–103. doi:10.1177/1753425909339231.CrossRefPubMed

19.

Hume GE, Fowler EV, Doecke J, et al. Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn’s disease in an Australian population. Inflamm Bowel Dis. 2008;14:585–590. doi:10.1002/ibd.20362.CrossRefPubMed

20.

Bank S, Skytt Andersen P, Burisch J, et al. 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. PLoS ONE. 2014;9:e98815. doi:10.1371/journal.pone.0098815.CrossRefPubMedPubMedCentral

21.

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.CrossRefPubMed

22.

Di Rienzo A. Population genetics models of common diseases. Curr Opin Genet Dev. 2006;16:630–636. doi:10.1016/j.gde.2006.10.002.CrossRefPubMed

23.

Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001;69:124–137. doi:10.1086/321272.CrossRefPubMedPubMedCentral

24.

Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology.. 2012;142:46–54-e42. doi:10.1053/j.gastro.2011.10.001. (quiz e30).CrossRefPubMed

25.

Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–753. doi:10.1136/gut.2005.082909.CrossRefPubMedPubMedCentral

26.

Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514.CrossRefPubMed

27.

Walmsley RS, Ayres RC, Pounder RE, Allan RN. A simple clinical colitis activity index. Gut. 1998;43:29–32.CrossRefPubMedPubMedCentral

28.

Pestaner JP, Bibbo M, Bobroski L, Seshamma T, Bagasra O. Potential of the in situ polymerase chain reaction in diagnostic cytology. Acta Cytol. 1994;38:676–680.PubMed

29.

Rigoli L, Romano C, Caruso RA, et al. Clinical significance of NOD2/CARD15 and Toll-like receptor 4 gene single nucleotide polymorphisms in inflammatory bowel disease. World J Gastroenterol. 2008;14:4454–4461.CrossRefPubMedPubMedCentral

30.

Leite TK, Fonseca RM, de Franca NM, Parra EJ, Pereira RW. Genomic ancestry, self-reported “color” and quantitative measures of skin pigmentation in Brazilian admixed siblings. PLoS ONE. 2011;6:e27162. doi:10.1371/journal.pone.0027162.CrossRefPubMedPubMedCentral

31.

Pena SD, Di Pietro G, Fuchshuber-Moraes M, et al. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE. 2011;6:e17063. doi:10.1371/journal.pone.0017063.CrossRefPubMedPubMedCentral

32.

Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962. doi:10.1038/ng.175.CrossRefPubMedPubMedCentral

33.

Bonen DK, Ogura Y, Nicolae DL, et al. Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology. 2003;124:140–146. doi:10.1053/gast.2003.50019.CrossRefPubMed

34.

Riis L, Vind I, Vermeire S, et al. The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel Dis. 2007;13:24–32. doi:10.1002/ibd.20047.CrossRefPubMed

35.

Kenny EE, Pe’er I, Karban A, et al. A genome-wide scan of Ashkenazi Jewish Crohn’s disease suggests novel susceptibility loci. PLoS Genet. 2012;8:e1002559. doi:10.1371/journal.pgen.1002559.CrossRefPubMedPubMedCentral

36.

Peter I, Mitchell AA, Ozelius L, et al. Evaluation of 22 genetic variants with Crohn’s disease risk in the Ashkenazi Jewish population: a case-control study. BMC Med Genet. 2011;12:63. doi:10.1186/1471-2350-12-63.CrossRefPubMedPubMedCentral

37.

Adeyanju O, Okou DT, Huang C, et al. Common NOD2 risk variants in African Americans with Crohn’s disease are due exclusively to recent Caucasian admixture. Inflamm Bowel Dis. 2012;18:2357–2359. doi:10.1002/ibd.22944.CrossRefPubMedPubMedCentral

38.

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.CrossRefPubMed

39.

Leong RW, Armuzzi A, Ahmad T, et al. NOD2/CARD15 gene polymorphism and Crohn’s disease in the Chinese population. Aliment Pharmacol Ther. 2003;17:1465–1470.CrossRefPubMed

40.

Queiroz DM, Oliveira AG, Saraiva IE, et al. Immune response and gene polymorphism profiles in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2009;15:353–358. doi:10.1002/ibd.20757.CrossRefPubMed

41.

Baptista ML, Amarante H, Picheth G, et al. CARD15 and IL23R influences Crohn’s disease susceptibility but not disease phenotype in a Brazilian population. Inflamm Bowel Dis. 2008;14:674–679. doi:10.1002/ibd.20372.CrossRefPubMed

42.

Lins TC, Vieira RG, Abreu BS, Grattapaglia D, Pereira RW. Genetic composition of Brazilian population samples based on a set of twenty-eight ancestry informative SNPs. Am J Hum Biol. 2010;22:187–192. doi:10.1002/ajhb.20976.PubMed

43.

Sans M. Admixture studies in Latin America: from the 20th to the 21st century. Hum Biol. 2000;72:155–177.PubMed

44.

Parra FC, Amado RC, Lambertucci JR, et al. Color and genomic ancestry in Brazilians. Proc Natl Acad Sci USA. 2003;100:177–182. doi:10.1073/pnas.0126614100.CrossRefPubMed

45.

de Neves Saloum, Manta F, Pereira R, Vianna R, et al. Revisiting the genetic ancestry of Brazilians using autosomal AIM-Indels. PLoS ONE. 2013;8:e75145. doi:10.1371/journal.pone.0075145.CrossRef

46.

Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–1125. doi:10.1038/ng.717.CrossRefPubMedPubMedCentral

47.

Hirano A, Yamazaki K, Umeno J, et al. Association study of 71 European Crohn’s disease susceptibility loci in a Japanese population. Inflamm Bowel Dis. 2013;19:526–533. doi:10.1097/MIB.0b013e31828075e7.CrossRefPubMed

48.

Chen L, Lin MJ, Zhan LL, Lv XP. Analysis of TLR4 and TLR2 polymorphisms in inflammatory bowel disease in a Guangxi Zhuang population. World J Gastroenterol. 2012;18:6856–6860. doi:10.3748/wjg.v18.i46.6856.CrossRefPubMedPubMedCentral

49.

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.CrossRefPubMed

50.

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. doi:10.1016/S0140-6736(00)05063-7.CrossRefPubMed

51.

Heresbach D, Gicquel-Douabin V, Birebent B, et al. NOD2/CARD15 gene polymorphisms in Crohn’s disease: a genotype–phenotype analysis. Eur J Gastroenterol Hepatol. 2004;16:55–62.CrossRefPubMed

52.

Sugimura K, Taylor KD, Lin YC, et al. A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. Am J Hum Genet. 2003;72:509–518. doi:10.1086/367848.CrossRefPubMedPubMedCentral

53.

Lv C, Yang X, Zhang Y, et al. Confirmation of three inflammatory bowel disease susceptibility loci in a Chinese cohort. Int J Colorectal Dis. 2012;27:1465–1472. doi:10.1007/s00384-012-1450-6.CrossRefPubMed

54.

Chua KH, Hilmi I, Ng CC, et al. Identification of NOD2/CARD15 mutations in Malaysian patients with Crohn’s disease. J Dig Dis. 2009;10:124–130. doi:10.1111/j.1751-2980.2009.00374.x.CrossRefPubMed

55.

Tukel T, Shalata A, Present D, et al. Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families. Am J Hum Genet. 2004;74:623–636. doi:10.1086/382226.CrossRefPubMedPubMedCentral

56.

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.CrossRefPubMed

57.

Strober W, Kitani A, Fuss I, Asano N, Watanabe T. The molecular basis of NOD2 susceptibility mutations in Crohn’s disease. Mucosal Immunol. 2008;1:S5–S9. doi:10.1038/mi.2008.42.CrossRefPubMedPubMedCentral

58.

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.CrossRefPubMedPubMedCentral

59.

Torok HP, Glas J, Tonenchi L, Mussack T, Folwaczny C. Polymorphisms of the lipopolysaccharide-signaling 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. doi:10.1016/j.clim.2004.03.002.CrossRefPubMed

60.

Nimmo ER, Stevens C, Phillips AM, et al. TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn’s disease. Gastroenterology.. 2011;141:972–981-e1-2. doi:10.1053/j.gastro.2011.05.043.CrossRefPubMed

61.

Adams AT, Kennedy NA, Hansen R, et al. Two-stage genome-wide methylation profiling in childhood-onset Crohn’s disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci. Inflamm Bowel Dis. 2014;20:1784–1793. doi:10.1097/MIB.0000000000000179.CrossRefPubMedPubMedCentral

62.

Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology. 2013;145:293–308. doi:10.1053/j.gastro.2013.05.050.CrossRefPubMedPubMedCentral

63.

Stranger BE, Stahl EA, Raj T. Progress and promise of genome-wide association studies for human complex trait genetics. Genetics. 2011;187:367–383. doi:10.1534/genetics.110.120907.CrossRefPubMedPubMedCentral

64.

Sanderson IR, Walker WA. TLRs in the gut. I. The role of TLRs/Nods in intestinal development and homeostasis. Am J Physiol Gastrointest Liver Physiol.. 2007;292:G6–G10. doi:10.1152/ajpgi.00275.2006.CrossRefPubMed

65.

Kranich J, Maslowski KM, Mackay CR. Commensal flora and the regulation of inflammatory and autoimmune responses. Semin Immunol. 2011;23:139–145. doi:10.1016/j.smim.2011.01.011.CrossRefPubMed

Titel: Common NOD2/CARD15 and TLR4 Polymorphisms Are Associated with Crohn’s Disease Phenotypes in Southeastern Brazilians
verfasst von: Yolanda F. M. Tolentino
Paula Peruzzi Elia
Homero Soares Fogaça
Antonio José V. Carneiro
Cyrla Zaltman
Rodrigo Moura-Neto
Ronir Raggio Luiz
Maria da Gloria C. Carvalho
Heitor S. de Souza
Publikationsdatum: 23.04.2016
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 9/2016
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-016-4172-8

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Common NOD2/CARD15 and TLR4 Polymorphisms Are Associated with Crohn’s Disease Phenotypes in Southeastern Brazilians

Abstract

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Methods

Results

Conclusion

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