Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Brazilian research foundations CNPq and FAPERJ for their financial support.

Funding

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro-FAPERJ and Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq.

Author contributions

Tolentino Y.F.M. and Elia P.P. participated in the conception and design of the study, the acquisition, analysis, and interpretation of data, and the drafting of the manuscript; Fogaça H., Carneiro A.J.V., and Zaltman C. participated in the acquisition, analysis, and interpretation of the data and the drafting of parts of the manuscript; Moura-Neto R. and Luiz R.R. participated in the design of the study, analysis and interpretation of data, and critically revised the manuscript for important intellectual content; Carvalho M.G.C. and de Souza H.S.P. participated in the conception and design of the study, obtained funding, analyzed and interpreted data, and critically revised the manuscript for important intellectual content; All authors gave final approval of the submitted version of the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Serviço de Gastroenterologia, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil

      Yolanda F. M. Tolentino, Paula Peruzzi Elia, Homero Soares Fogaça, Antonio José V. Carneiro, Cyrla Zaltman & Heitor S. de Souza

    2. Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil

      Rodrigo Moura-Neto

    3. Instituto de Estudos de Saúde Coletiva (IESC), Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21944-970, Brazil

      Ronir Raggio Luiz

    4. Laboratório de Patologia Molecular, Departamento de Patologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil

      Maria da Gloria C. Carvalho

    5. Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Duque de Caxias, Rio de Janeiro, 25250-020, Brazil

      Rodrigo Moura-Neto

    6. D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ, 22281-100, Brazil

      Heitor S. de Souza

    Authors
    1. Yolanda F. M. Tolentino
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Paula Peruzzi Elia
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Homero Soares Fogaça
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Antonio José V. Carneiro
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Cyrla Zaltman
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rodrigo Moura-Neto
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ronir Raggio Luiz
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Maria da Gloria C. Carvalho
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Heitor S. de Souza
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Heitor S. de Souza.

    Ethics declarations

    Conflict of interest

    The authors have no conflicts of interest to disclose.

    Additional information

    Yolanda F. M. Tolentino and Paula Peruzzi Elia have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOC 72 kb)

    Supplementary material 2 (DOC 74 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Tolentino, Y.F.M., Elia, P.P., Fogaça, H.S. et al. Common NOD2/CARD15 and TLR4 Polymorphisms Are Associated with Crohn’s Disease Phenotypes in Southeastern Brazilians. Dig Dis Sci 61, 2636–2647 (2016). https://doi.org/10.1007/s10620-016-4172-8

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10620-016-4172-8

    Keywords

    Search

    Navigation