International Journal of Colorectal Disease

, Volume 25, Issue 2, pp 161–168 | Cite as

Differential effects of NOD2 polymorphisms on colorectal cancer risk: a meta-analysis

  • Yun Tian
  • Yi Li
  • Zhenhua Hu
  • Daqing Wang
  • Xiyang Sun
  • Changshan RenEmail author
Original Article



Since Kurzawski et al. described an association between the 3020insC NOD2 single nucleotide polymorphism and the risk of colorectal cancer(CRC) in 2004, reports published in the past several years have controversial results regarding the relationship between the development of CRC and NOD2 gene polymorphisms. To clarify the potential role of NOD2 P286S, R702W, G908R, and 3020insC polymorphisms in CRC patients, we have undertaken a systematic review and meta-analysis of published articles.

Materials and methods

Studies reporting on NOD2 polymorphisms and CRC were searched in the PubMed, EMBASE, and the Science Citation Index from the inception of each database to May, 2009. The search strategy included the keywords “CRC”, “colon cancer”, “rectal cancer”, “polymorphism”, and “NOD2/CARD15”.


Eight eligible case-control studies about Caucasians from four countries contributed data on 5,888 subjects (cases: 3,524; controls: 2,364). Compared to the wild genotype, the R702W, G908R, and 3020insC polymorphisms were associated with an increased risk of CRC (odds ratio (OR): 1.59, 1.98, 1.44; 95% confidence interval (CI): 1.09–2.32, 1.14–3.44, 1.13–1.84; P = 0.02, 0.01, 0.003). However, P268S polymorphism did not influence CRC risk (OR: 1.27; CI: 0.32–5.00; P = 0.73).


These findings indicate that NOD2 R702W, G908R, and 3020insC polymorphisms contribute to CRC susceptibility in Caucasians. Meta-analysis of these polymorphisms in NOD2 gene will help determine their role in CRC carcinogenesis.


Colorectal cancer Polymorphism NOD2/CARD15 



We thank Dr. Guan (Medical School, Nanjing University) for his critical review of the manuscript and evaluation of the statistical quality of the meta-analysis.

Declaration of personal interests

We are indebted to the authors of the primary studies

Declaration of funding interests



  1. 1.
    Capurso G, Marignani M, Delle Fave G (2006) Probiotics and the incidence of colorectal cancer: when evidence is not evident. Dig Liver Dis 38(Suppl 2):S277–S282CrossRefPubMedGoogle Scholar
  2. 2.
    Kim HJ, Yu MH, Kim H, Byun J, Lee C (2008) Noninvasive molecular biomarkers for the detection of colorectal cancer. BMB Rep 41:685–692PubMedGoogle Scholar
  3. 3.
    Loffler I, Grun M, Bohmer FD, Rubio I (2008) Role of cAMP in the promotion of colorectal cancer cell growth by prostaglandin E2. BMC Cancer 8:380CrossRefPubMedGoogle Scholar
  4. 4.
    Takahashi H, Inamori M (2009) Lifestyle-related disease and colorectal cancer. Intern Med 48:121CrossRefPubMedGoogle Scholar
  5. 5.
    Kasztelan-Szczerbinska B, Cichoz-Lach H, Slomka M (2008) Colorectal cancer as a health care problem: evaluation of the current diagnostic options. Pol Arch Med Wewn 118:224–227PubMedGoogle Scholar
  6. 6.
    Velculescu VE (2008) Defining the blueprint of the cancer genome. Carcinogenesis 29:1087–1091CrossRefPubMedGoogle Scholar
  7. 7.
    Hisamuddin IM, Yang VW (2004) Genetics of colorectal cancer. MedGenMed 6:13PubMedGoogle Scholar
  8. 8.
    Cheah PY (2009) Recent advances in colorectal cancer genetics and diagnostics. Crit Rev Oncol Hematol 69:45–55CrossRefPubMedGoogle Scholar
  9. 9.
    Chu E (2009) Clinical colorectal cancer: "2008—the year in review". Clin Colorectal Cancer 8:9–10CrossRefPubMedGoogle Scholar
  10. 10.
    Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S et al (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357:1925–1928CrossRefPubMedGoogle Scholar
  11. 11.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603CrossRefPubMedGoogle Scholar
  12. 12.
    Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606CrossRefPubMedGoogle Scholar
  13. 13.
    Inohara C, McDonald C, Nunez G (2005) NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383CrossRefPubMedGoogle Scholar
  14. 14.
    Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872CrossRefPubMedGoogle Scholar
  15. 15.
    Inohara N, Nunez G (2001) The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20:6473–6481CrossRefPubMedGoogle Scholar
  16. 16.
    Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J et al (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278:5509–5512CrossRefPubMedGoogle Scholar
  17. 17.
    Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR et al (2001) CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2:736–742CrossRefPubMedGoogle Scholar
  18. 18.
    Angeletti S, Galluzzo S, Santini D, Ruzzo A, Vincenzi B, Ferraro E et al (2009) NOD2/CARD15 polymorphisms impair innate immunity and increase susceptibility to gastric cancer in an Italian population. Hum Immunol 70(9):729–732CrossRefPubMedGoogle Scholar
  19. 19.
    Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD (1997) The codependence of angiogenesis and chronic inflammation. FASEB J 11:457–465PubMedGoogle Scholar
  20. 20.
    Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ (2000) Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60:184–190PubMedGoogle Scholar
  21. 21.
    Nakajima N, Kuwayama H, Ito Y, Iwasaki A, Arakawa Y (1997) Helicobacter pylori, neutrophils, interleukins, and gastric epithelial proliferation. J Clin Gastroenterol 25(Suppl 1):S198–S202CrossRefPubMedGoogle Scholar
  22. 22.
    Bernstein CN, Blanchard JF, Kliewer E, Wajda A (2001) Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 91:854–862CrossRefPubMedGoogle Scholar
  23. 23.
    Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen TI (2005) Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol 100:2724–2729CrossRefPubMedGoogle Scholar
  24. 24.
    Leshinsky-Silver E, Karban A, Buzhakor E, Fridlander M, Yakir B, Eliakim R et al (2005) Is age of onset of Crohn's disease governed by mutations in NOD2/caspase recruitment domains 15 and Toll-like receptor 4? Evaluation of a pediatric cohort. Pediatr Res 58:499–504CrossRefPubMedGoogle Scholar
  25. 25.
    Alhopuro P, Ahvenainen T, Mecklin JP, Juhola M, Jarvinen HJ, Karhu A et al (2004) NOD2 3020insC alone is not sufficient for colorectal cancer predisposition. Cancer Res 64:7245–7247CrossRefPubMedGoogle Scholar
  26. 26.
    Kurzawski G, Suchy J, Kladny J, Grabowska E, Mierzejewski M, Jakubowska A et al (2004) The NOD2 3020insC mutation and the risk of colorectal cancer. Cancer Res 64:1604–1606CrossRefPubMedGoogle Scholar
  27. 27.
    Lakatos PL, Hitre E, Szalay F, Zinober K, Fuszek P, Lakatos L et al (2007) Common NOD2/CARD15 variants are not associated with susceptibility or the clinicopathologic characteristics of sporadic colorectal cancer in Hungarian patients. BMC Cancer 7:54CrossRefPubMedGoogle Scholar
  28. 28.
    Papaconstantinou I, Theodoropoulos G, Gazouli M, Panoussopoulos D, Mantzaris GJ, Felekouras E et al (2005) Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population. Int J Cancer 114:433–435CrossRefPubMedGoogle Scholar
  29. 29.
    Roberts RL, Gearry RB, Allington MD, Morrin HR, Robinson BA, Frizelle FA (2006) Caspase recruitment domain-containing protein 15 mutations in patients with colorectal cancer. Cancer Res 66:2532–2535CrossRefPubMedGoogle Scholar
  30. 30.
    Suchy J, Klujszo-Grabowska E, Kladny J, Cybulski C, Wokolorczyk D, Szymanska-Pasternak J et al (2008) Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk. BMC Cancer 8:112CrossRefPubMedGoogle Scholar
  31. 31.
    Szeliga J, Sondka Z, Jackowski M, Jarkiewicz-Tretyn J, Tretyn A, Malenczyk M (2008) NOD2/CARD15 polymorphism in patients with rectal cancer. Med Sci Monit 14:CR480–CR484PubMedGoogle Scholar
  32. 32.
    Tuupanen S, Alhopuro P, Mecklin JP, Jarvinen H, Aaltonen LA (2007) No evidence for association of NOD2 R702W and G908R with colorectal cancer. Int J Cancer 121:76–79CrossRefPubMedGoogle Scholar
  33. 33.
    Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF (1999) Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 354:1896–1900CrossRefPubMedGoogle Scholar
  34. 34.
    Hampe J, Grebe J, Nikolaus S, Solberg C, Croucher PJ, Mascheretti S et al (2002) Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study. Lancet 359:1661–1665CrossRefPubMedGoogle Scholar
  35. 35.
    Inohara N, Ogura Y, Chen FF, Muto A, Nunez G (2001) Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 276:2551–2554CrossRefPubMedGoogle Scholar
  36. 36.
    Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276:4812–4818CrossRefPubMedGoogle Scholar
  37. 37.
    Chen F, Castranova V, Shi X (2001) New insights into the role of nuclear factor-kappaB in cell growth regulation. Am J Pathol 159:387–397PubMedGoogle Scholar
  38. 38.
    Dejardin E, Deregowski V, Chapelier M, Jacobs N, Gielen J, Merville MP et al (1999) Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma cells. Oncogene 18:2567–2577CrossRefPubMedGoogle Scholar
  39. 39.
    Gilmore TD, Koedood M, Piffat KA, White DW (1996) Rel/NF-kappaB/IkappaB proteins and cancer. Oncogene 13:1367–1378PubMedGoogle Scholar
  40. 40.
    Mukhopadhyay T, Roth JA, Maxwell SA (1995) Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene 11:999–1003PubMedGoogle Scholar
  41. 41.
    Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM et al (1997) Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest 100:2952–2960CrossRefPubMedGoogle Scholar
  42. 42.
    Huzarski T, Lener M, Domagala W, Gronwald J, Byrski T, Kurzawski G et al (2005) The 3020insC allele of NOD2 predisposes to early onset breast cancer. Breast Cancer Res Treat 89:91–93CrossRefPubMedGoogle Scholar
  43. 43.
    Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT et al (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7:27–38CrossRefPubMedGoogle Scholar
  44. 44.
    Yang SK, Loftus EV Jr, Sandborn WJ (2001) Epidemiology of inflammatory bowel disease in Asia. Inflamm Bowel Dis 7:260–270CrossRefPubMedGoogle Scholar
  45. 45.
    Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y et al (2002) Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 123:86–91CrossRefPubMedGoogle Scholar
  46. 46.
    Cavanaugh JA, Adams KE, Quak EJ, Bryce ME, O'Callaghan NJ, Rodgers HJ et al (2003) CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population. Ann Hum Genet 67:35–41CrossRefPubMedGoogle Scholar
  47. 47.
    Andersen V, Agerstjerne L, Jensen D, Ostergaard M, Saebo M, Hamfjord J et al (2009) The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study. BMC Med Genet 10:18CrossRefPubMedGoogle Scholar
  48. 48.
    Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Kearney J et al (1994) A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. men. J Natl Cancer Inst 86:183–191CrossRefPubMedGoogle Scholar
  49. 49.
    Ernst A, Jacobsen B, Ostergaard M, Okkels H, Andersen V, Dagiliene E et al (2007) Mutations in CARD15 and smoking confer susceptibility to Crohn's disease in the Danish population. Scand J Gastroenterol 42:1445–1451CrossRefPubMedGoogle Scholar
  50. 50.
    Hansen RD, Sorensen M, Tjonneland A, Overvad K, Wallin H, Raaschou-Nielsen O et al (2008) A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a Danish prospective case-cohort study. BMC Cancer 8:54CrossRefPubMedGoogle Scholar
  51. 51.
    Anderson JC, Attam R, Alpern Z, Messina CR, Hubbard P, Grimson R et al (2003) Prevalence of colorectal neoplasia in smokers. Am J Gastroenterol 98:2777–2783CrossRefPubMedGoogle Scholar
  52. 52.
    Liang PS, Chen TY, Giovannucci E (2009) Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer 124:2406–2415CrossRefPubMedGoogle Scholar
  53. 53.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M et al (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85CrossRefPubMedGoogle Scholar
  54. 54.
    Aaltonen L, Johns L, Jarvinen H, Mecklin JP, Houlston R (2007) Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res 13:356–361CrossRefPubMedGoogle Scholar
  55. 55.
    Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S et al (2008) Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40:1426–1435CrossRefPubMedGoogle Scholar
  56. 56.
    Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39:984–988CrossRefPubMedGoogle Scholar
  57. 57.
    Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM et al (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39:989–994CrossRefPubMedGoogle Scholar
  58. 58.
    Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM et al (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40:623–630CrossRefPubMedGoogle Scholar
  59. 59.
    Tenesa A, Farrington SM, Prendergast JG, Porteous ME, Walker M, Haq N et al (2008) Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40:631–637CrossRefPubMedGoogle Scholar
  60. 60.
    Jaeger E, Webb E, Howarth K, Carvajal-Carmona L, Rowan A, Broderick P et al (2008) Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40:26–28CrossRefPubMedGoogle Scholar
  61. 61.
    Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4:45–61CrossRefPubMedGoogle Scholar
  62. 62.
    Ioannidis JP (2003) Genetic associations: false or true? Trends Mol Med 9:135–138CrossRefPubMedGoogle Scholar
  63. 63.
    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309CrossRefPubMedGoogle Scholar
  64. 64.
    Guo QS, Xia B, Jiang Y, Qu Y, Li J (2004) NOD2 3020insC frameshift mutation is not associated with inflammatory bowel disease in Chinese patients of Han nationality. World J Gastroenterol 10:1069–1071PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Yun Tian
    • 1
  • Yi Li
    • 2
  • Zhenhua Hu
    • 3
  • Daqing Wang
    • 1
  • Xiyang Sun
    • 1
  • Changshan Ren
    • 1
    Email author
  1. 1.Tumor InstituteChina Medical UniversityShenyangChina
  2. 2.Department of General Surgery, Jinling HospitalMedical School of Nanjing UniversityNanjingChina
  3. 3.Department of PathologyJilin UniversityChangchunChina

Personalised recommendations