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Ethnic differences in cytokine gene polymorphisms: potential implications for cancer development

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Abstract

Differences in incidence and outcome of cancer among ethnic groups may be explained by biological and/or socio-economic factors. Genetic variations that affect chronic inflammation, a potentially important risk factor for carcinogenesis, may differ across ethnic groups. Such differences may help explain cancer disparities among these groups. Single nucleotide polymorphisms (SNPs) within cytokine genes can affect cytokine levels and the degree of inflammation. Associations between cancer and some cytokine SNPs have been suggested. However, these have not been consistently replicated among populations, suggesting that SNP function may differ according to ethnicity, or that SNPs alone do not completely account for regulation of inflammation. We examined seven polymorphisms in African-American (n = 294) and Caucasian (n = 299) newborns in Louisiana: IL1B-511C > T, IL1B-31T > C, IL1B + 3954C > T, IL1RN*2, IL10-1082G > A, IL10-592C > A, and TNF-308G > A. African-American newborns had significantly higher frequencies of IL1B-511T, IL1B-31C, IL10-1082A and IL10-592A alleles and complete linkage equilibrium between IL1B + 3954 and IL1B-31. In contrast, IL1B + 3954T, IL1RN*2, and TNF-308A were more frequent in Caucasian newborns and exhibited strong linkage disequilibrium between IL1B + 3954 and IL1B-31. All allelic frequencies were significantly different between groups. We hypothesize that these dissimilarities may contribute to differences in the inflammatory response and cancer incidence and mortality between African-Americans and Caucasians in Louisiana.

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References

  1. Alpizar-Alpizar W, Perez-Perez GI, Une C, Cuenca P, Sierra R (2005) Association of interleukin-1B and interleukin-1RN polymorphisms with gastric cancer in a high-risk population of Costa Rica. Clin Exp Med 5:169–176

    Article  PubMed  CAS  Google Scholar 

  2. Balasubramanian SP, Azmy IA, Higham SE, Wilson AG, Cross SS, Cox A, Brown NJ, Reed MW (2006) Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review. BMC Cancer 6:188

    Article  PubMed  CAS  Google Scholar 

  3. Barber MD, Powell JJ, Lynch SF, Fearon KC, Ross JA (2000) A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer. Br J Cancer 83:1443–1447

    Article  PubMed  CAS  Google Scholar 

  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  5. Beales IL, Calam J (1998) Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut 42:227–234

    Article  PubMed  CAS  Google Scholar 

  6. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL (1995) Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 46:32–41

    PubMed  Google Scholar 

  7. Camargo MC, Mera R, Correa P, Peek RM Jr, Fontham ETH, Goodman KJ, Piazuelo MB, Sicinschi LA, Zabaleta J, Schneider BG (2006) Interleukin-1B and Interleukin 1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15:1674–1687

    Article  PubMed  CAS  Google Scholar 

  8. Camargo MC, Yepez MC, Ceron C, Guerrero N, Bravo LE, Correa P, Fontham ET (2004) Age at acquisition of Helicobacter pylori infection: comparison of two areas with contrasting risk of gastric cancer. Helicobacter 9:262–270

    Article  PubMed  Google Scholar 

  9. Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle C, Rogus J, Beck JD, Offenbacher S, Cork MJ, Rafie-Kolpin M, Hsieh CM, Kornman KS, Duff GW (2006) Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 15:519–529

    Article  PubMed  CAS  Google Scholar 

  10. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  11. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P (1999) Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 42:1101–1108

    Article  PubMed  CAS  Google Scholar 

  12. Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP (1991) Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266:10331–10336

    PubMed  CAS  Google Scholar 

  13. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402

    Article  PubMed  CAS  Google Scholar 

  14. El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ, Fraumeni JF Jr, Chow WH (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201

    Article  PubMed  CAS  Google Scholar 

  15. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  PubMed  CAS  Google Scholar 

  16. Goodman KJ, Correa P (1995) The transmission of Helicobacter pylori: a critical review of the evidence. Int J Epidemiol 24:875–887

    Article  PubMed  CAS  Google Scholar 

  17. Granowitz EV, Clark BD, Mancilla J, Dinarello CA (1991) Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem 266:14147–14150

    PubMed  CAS  Google Scholar 

  18. Hall SK, Perregaux DG, Gabel CA, Woodworth T, Durham LK, Huizinga TW, Breedveld FC, Seymour AB (2004) Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum 50:1976–1983

    Article  PubMed  CAS  Google Scholar 

  19. Hassan MI, Aschner Y, Manning CH, Xu J, Aschner JL (2003) Racial differences in selected cytokine allelic and genotypic frequencies among healthy, pregnant women in North Carolina. Cytokine 21:10–16

    Article  PubMed  CAS  Google Scholar 

  20. Havranek E, Howell WM, Fussell HM, Whelan JA, Whelan MA, Pandha HS (2005) An interleukin-10 promoter polymorphism may influence tumor development in renal cell carcinoma. J Urol 173:709–712

    Article  PubMed  CAS  Google Scholar 

  21. Hefler LA, Ludwig E, Lebrecht A, Zeillinger R, Tong-Cacsire D, Koelbl H, Leodolter S, Tempfer CB (2002) Polymorphisms of the interleukin-1 gene cluster and ovarian cancer. J Soc Gynecol Investig 9:386–390

    Article  PubMed  CAS  Google Scholar 

  22. Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ (2002) Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2:560–567

    Article  PubMed  CAS  Google Scholar 

  23. Hu Z, Shao M, Chen Y, Zhou J, Qian J, Xu L, Ma H, Wang X, Xu Y, Lu D, Shen H (2006) Allele 2 of the interleukin-1 receptor antagonist gene (IL1RN*2) is associated with a decreased risk of primary lung cancer. Cancer Lett 236:269–275

    Article  PubMed  CAS  Google Scholar 

  24. Hurme M, Santtila S (1998) IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunology 28:2598–2602

    Article  CAS  Google Scholar 

  25. Hwang IR, Kodama T, Kikuchi S, Sakai K, Peterson LE, Graham DY, Yamaoka Y (2002) Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology 123:1793–1803

    Article  PubMed  CAS  Google Scholar 

  26. IARC (1994) IARC monograph on the evaluation of carcinogenic risks to humans:schistosomes, liver flukes and Helicobacter pylori. IARC 61:1–241

    Google Scholar 

  27. Kato S, Onda M, Yamada S, Matsuda N, Tokunaga A, Matsukura N (2001) Association of the interleukin-1 beta genetic polymorphism and gastric cancer risk in Japanese. J Gastroenterol 36:696–699

    Article  PubMed  CAS  Google Scholar 

  28. Kroeger KM, Carville KS, Abraham LJ (1997) The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 34:391–399

    Article  PubMed  CAS  Google Scholar 

  29. Lee JY, Kim HY, Kim KH, Kim SM, Jang MK, Park JY, Lee JH, Kim JH, Yoo JY (2005) Association of polymorphism of IL-10 and TNF-A genes with gastric cancer in Korea. Cancer Lett 225:207–214

    Article  PubMed  CAS  Google Scholar 

  30. Lee KM, Park SK, Hamajima N, Tajima K, Choi JY, Noh DY, Ahn SH, Yoo KY, Hirvonen A, Kang D (2006) Genetic polymorphisms of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) and breast cancer risk in Korean women. Breast Cancer Res Treat 96:197–202

    Article  PubMed  CAS  Google Scholar 

  31. Lee SG, Kim B, Choi W, Lee I, Choi J, Song K (2003) Lack of association between pro-inflammatory genotypes of the interleukin-1 (IL-1B -31 C/+ and IL-1RN *2/*2) and gastric cancer/duodenal ulcer in Korean population. Cytokine 21:167–171

    Article  PubMed  CAS  Google Scholar 

  32. Liu J, Zhai X, Jin G, Hu Z, Wang S, Wang X, Qin J, Gao J, Ma H, Wang X, Wei Q, Shen H (2006) Functional variants in the promoter of interleukin-1beta are associated with an increased risk of breast cancer: a case-control analysis in a Chinese population. Int J Cancer 118:2554–2558

    Article  PubMed  CAS  Google Scholar 

  33. Liu K, Muse SV (2005) PowerMarker: an integrated analysis environment for genetic marker analysis. Bioinformatics 21:2128–2129

    Article  PubMed  CAS  Google Scholar 

  34. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro AC, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simoes M (2003) A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125:364–371

    Article  PubMed  CAS  Google Scholar 

  35. Machado JC, Pharoah P, Sousa S, Carvalho R, Oliveira C, Figueiredo C, Amorim A, Seruca R, Caldas C, Carneiro F, Sobrinho-Simoes M (2001) Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 121:823–829

    Article  PubMed  CAS  Google Scholar 

  36. Mege JL, Meghari S, Honstettre A, Capo C, Raoult D (2006) The two faces of interleukin 10 in human infectious diseases. Lancet Infect Dis 6:557–569

    Article  PubMed  CAS  Google Scholar 

  37. Michaud DS, Daugherty SE, Berndt SI, Platz EA, Yeager M, Crawford ED, Hsing A, Huang WY, Hayes RB (2006) Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res 66:4525–4530

    Article  PubMed  CAS  Google Scholar 

  38. Morgan DR, Dominguez RL, Keku TO, Heidt PE, Martin CF, Galanko JA, Omofoye OA, Sandler RS (2006) Gastric cancer and the high combination prevalence of host cytokine genotypes and Helicobacter pylori in Honduras. Clin Gastroenterol Hepatol 4:1103–1111

    Article  PubMed  CAS  Google Scholar 

  39. Moss SF, Blaser MJ (2005) Mechanisms of disease: Inflammation and the origins of cancer. Nat Clin Pract Oncol 2:90–97

    Article  PubMed  CAS  Google Scholar 

  40. National Cancer Institute (2006) State cancer profiles, http://www.statecancerprofiles.cancer.gov

  41. Ness RB, Haggerty CL, Harger G, Ferrell R (2004) Differential distribution of allelic variants in cytokine genes among African-Americans and white Americans. Am J Epidemiol 160:1033–1038

    Article  PubMed  Google Scholar 

  42. Nguyen DP, Genc M, Vardhana S, Babula O, Onderdonk A, Witkin SS (2004) Ethnic differences of polymorphisms in cytokine and innate immune system genes in pregnant women. Obstet Gynecol 104:293–300

    PubMed  CAS  Google Scholar 

  43. Nikolova PN, Pawelec GP, Mihailova SM, Ivanova MI, Myhailova AP, Baltadjieva DN, Marinova DI, Ivanova SS, Naumova EJ (2007) Association of cytokine gene polymorphisms with malignant melanoma in Caucasian population. Cancer Immunol Immunother 56:371–379

    Article  PubMed  CAS  Google Scholar 

  44. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    PubMed  Google Scholar 

  45. Rad R, Dossumbekova A, Neu B, Lang R, Bauer S, Saur D, Gerhard M, Prinz C (2004) Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 53:1082–1089

    Article  PubMed  CAS  Google Scholar 

  46. Rad R, Prinz C, Neu B, Neuhofer M, Zeitner M, Voland P, Becker I, Schepp W, Gerhard M (2003) Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. J Infect Dis 188:272–281

    Article  PubMed  CAS  Google Scholar 

  47. Santtila S, Savinainen K, Hurme M (1998) Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 47:195–198

    Article  PubMed  CAS  Google Scholar 

  48. Schottenfeld D, Beebe-Dimmer J (2006) Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin 56:69–83

    PubMed  Google Scholar 

  49. Seifart C, Plagens A, Dempfle A, Clostermann U, Vogelmeier C, von Wichert P, Seifart U (2005) TNF-alpha, TNF-beta, IL-6, and IL-10 polymorphisms in patients with lung cancer. Dis Markers 21:157–165

    PubMed  CAS  Google Scholar 

  50. Shacter E, Weitzman SA (2002) Chronic inflammation and cancer. Oncology (Williston. Park) 16:217–226 see also 229

    Google Scholar 

  51. Shih CM, Lee YL, Chiou HL, Chen W, Chang GC, Chou MC, Lin LY (2006) Association of TNF-alpha polymorphism with susceptibility to and severity of non-small cell lung cancer. Lung Cancer 52:15–20

    Article  PubMed  Google Scholar 

  52. Sicinschi LA, Lopez-Carrillo L, Camargo MC, Correa P, Sierra RA, Henry RR, Chen J, Zabaleta J, Piazuelo MB, Schneider BG (2006) Gastric cancer risk in a Mexican population: role of Helicobacter pylori CagA positive infection and polymorphisms in interleukin-1 and -10 genes. Int J Cancer 118:649–657

    Article  PubMed  CAS  Google Scholar 

  53. Snoussi K, Strosberg AD, Bouaouina N, Ben AS, Chouchane L (2005) Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6) associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw 16:253–260

    PubMed  CAS  Google Scholar 

  54. Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA (1995) -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 46:42–50

    PubMed  Google Scholar 

  55. Terry CF, Loukaci V, Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138–18144

    Article  PubMed  CAS  Google Scholar 

  56. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

    PubMed  CAS  Google Scholar 

  57. Uglialoro AM, Turbay D, Pesavento PA, Delgado JC, McKenzie FE, Gribben JG, Hartl D, Yunis EJ, Goldfeld AE (1998) Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens 52:359–367

    Article  PubMed  CAS  Google Scholar 

  58. Ward E, Jemal A, Cokkinides V, Singh GK, Cardinez C, Ghafoor A, Thun M (2004) Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 54:78–93

    PubMed  Google Scholar 

  59. Wen AQ, Wang J, Feng K, Zhu PF, Wang ZG, Jiang JX (2006) Effects of haplotypes in the interleukin 1beta promoter on lipopolysaccharide-induced interleukin 1beta expression. Shock 26:25–30

    Article  PubMed  CAS  Google Scholar 

  60. Witkin SS, Gerber S, Ledger WJ (2002) Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 34:204–209

    Article  PubMed  CAS  Google Scholar 

  61. Wu MS, Wu CY, Chen CJ, Lin MT, Shun CT, Lin JT (2003) Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int J Cancer 104:617–623

    Article  PubMed  CAS  Google Scholar 

  62. Zabaleta J, Camargo MC, Piazuelo MB, Fontham E, Schneider BG, Sicinschi LA, Ferrante W, Balart L, Correa P, Ochoa AC (2006) Association of interleukin-1beta gene polymorphisms with precancerous gastric lesions in African-Americans and Caucasians. Am J Gastroenterol 101:163–171

    Article  PubMed  CAS  Google Scholar 

  63. Zeng ZR, Hu PJ, Hu S, Pang RP, Chen MH, Ng M, Sung JJ (2003) Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut 52:1684–1689

    Article  PubMed  CAS  Google Scholar 

  64. Zhang WH, Wang XL, Zhou J, An LZ, Xie XD (2005) Association of interleukin-1B (IL-1B) gene polymorphisms with risk of gastric cancer in Chinese population. Cytokine 30:378–381

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank all the people from the Louisiana Public Health Laboratory Newborn Screening Program for providing us with the dried blood spots. This work was supported in part by a grant of the National Cancer Institute (PO1CA028842) and by a grant from the Health Excellence Fund of the Board of Regents of the State of Louisiana (HEF-2000-05-03).

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Correspondence to Jovanny Zabaleta.

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Zabaleta, J., Schneider, B.G., Ryckman, K. et al. Ethnic differences in cytokine gene polymorphisms: potential implications for cancer development. Cancer Immunol Immunother 57, 107–114 (2008). https://doi.org/10.1007/s00262-007-0358-4

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