Advertisement

Cancer Causes & Control

, Volume 19, Issue 2, pp 163–173 | Cite as

Joint effect between regular use of non-steroidal anti-inflammatory drugs, variants in inflammatory genes and risk of lymphoma

  • Birgit Hoeft
  • Nikolaus Becker
  • Evelin Deeg
  • Lars Beckmann
  • Alexandra Nieters
Original Paper

Abstract

Objective

Limited evidence suggests the importance of inflammatory processes for the etiology of lymphomas. To further research in this area, we investigated the role of genetic variants in key inflammatory factors, non-steroidal anti-inflammatory drug [NSAID] use, and their joint effect in lymphomagenesis.

Methods

The study comprised 710 case–control pairs, matched for gender, age, and study region. We examined the association of regular NSAID use and polymorphisms in prostaglandin-endoperoxide synthase-2 (COX2), prostaglandin E synthase (PTGES), interleukin-1 alpha (IL1A), IL-1 beta (IL1B), and IL-1 receptor antagonist (IL1RA), and lymphoma risk by applying logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI).

Results

Regular NSAID use was associated with a slightly reduced risk of B-NHL (OR = 0.8, 95% CI = 0.6–1.1). For T-NHL, the COX2 rs2745557 A-allele conferred a 2.2-fold (95% CI = 1.1–4.5) and homozygosis for the IL1RN rs454078 T-allele was associated with a 4.5-fold (95% CI = 1.4–13.9) elevated risk, however, based on sparse data. IL1 haplotype 5 was associated with a statistically significant 43% increased risk for B-NHL among non-regular users of NSAIDs, but a 70% decreased risk for regular users (p-value for interaction < 0.001).

Conclusions

These results suggest the relevance of joint effects between NSAID use and IL1 haplotypes on the risk of B-NHL.

Keywords

Lymphoma Non-steroidal anti-inflammatory drugs (NSAIDs) Single nucleotide polymorphism (SNP) 

Notes

Acknowledgments

We are indebted to the participants of the study and to the many colleagues who supported the performance of the study. A detailed list is presented in previous publications [53]. For excellent technical assistance we thank Marlen Auer, Bettina Ehret, and Sandra Patommel and Stefan Wilkening for his support with TaqMan genotyping. Furthermore, we thank Jutta Kneisel and Sabine Behrens for their help with drug coding and statistical analysis, respectively. The study was funded by the Federal Office for Radiation Protection (StSch4261 and StSch4420) and supported by a Deutsche Forschungsgemeinschaft Grant BE 3906//2-1 (LB). The European Community supported the set up of a common protocol for assessment of occupational exposures (SOC 98 201307 05F02) and implementation of additional study areas (QLK4-CT-2000-00422). Genotyping was supported by the German José Carreras Leukaemia foundation (DJCLS_R04/08).

References

  1. 1.
    Jaffé ES, Harris NL, Stein H, Vardiman JWE (2001) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, LyonGoogle Scholar
  2. 2.
    Levi F, Lucchini F, Negri E, La Vecchia C (2002) Trends in mortality from non-Hodgkin’s lymphomas. Leuk Res 26:903–908PubMedCrossRefGoogle Scholar
  3. 3.
    Cartwright R, Brincker H, Carli PM et al (1999) The rise in incidence of lymphomas in Europe 1985–1992. Eur J Cancer 35:627–633PubMedCrossRefGoogle Scholar
  4. 4.
    Grulich AE, Vajdic CM (2005) The epidemiology of non-Hodgkin lymphoma. Pathology 37:409–419PubMedCrossRefGoogle Scholar
  5. 5.
    Gandhi MK, Khanna R (2005) Viruses and lymphoma. Pathology 37:420–433PubMedCrossRefGoogle Scholar
  6. 6.
    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and cancer: how hot is the link? Biochem Pharmacol 72:1605–1621PubMedCrossRefGoogle Scholar
  7. 7.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRefGoogle Scholar
  8. 8.
    Bosetti C, Gallus S, La VC (2006) Aspirin and cancer risk: an updated quantitative review to 2005. Cancer Causes Control 17:871–888PubMedCrossRefGoogle Scholar
  9. 9.
    Friis S, Sorensen HT, McLaughlin JK, Johnsen SP, Blot WJ, Olsen JH (2003) A population-based cohort study of the risk of colorectal and other cancers among users of low-dose aspirin. Br J Cancer 88:684–688PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang Y, Holford TR, Leaderer B et al (2004) Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women. Cancer Causes Control 15:419–428PubMedCrossRefGoogle Scholar
  11. 11.
    Flick ED, Chan KA, Bracci PM, Holly EA (2006) Use of nonsteroidal antiinflammatory drugs and non-Hodgkin lymphoma: a population-based case–control study. Am J Epidemiol 164:497–504PubMedCrossRefGoogle Scholar
  12. 12.
    Rosenberg L, Palmer JR, Zauber AG et al (1995) Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin’s lymphoma, testis, Hodgkin’s disease, thyroid, and liver. Am J Epidemiol 141:1153–1160PubMedGoogle Scholar
  13. 13.
    Bernstein L, Ross RK (1992) Prior medication use and health history as risk factors for non-Hodgkin’s lymphoma: preliminary results from a case–control study in Los Angeles County. Cancer Res 52:5510s–5515sPubMedGoogle Scholar
  14. 14.
    Cerhan JR, Anderson KE, Janney CA, Vachon CM, Witzig TE, Habermann TM (2003) Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma. Int J Cancer 106:784–788PubMedCrossRefGoogle Scholar
  15. 15.
    Kato I, Koenig KL, Shore RE et al (2002) Use of anti-inflammatory and non-narcotic analgesic drugs and risk of non-Hodgkin’s lymphoma (NHL) (United States). Cancer Causes Control 13:965–974PubMedCrossRefGoogle Scholar
  16. 16.
    Chang ET, Smedby KE, Hjalgrim H et al (2005) Medication use and risk of non-Hodgkin’s lymphoma. Am J Epidemiol 162:965–974PubMedCrossRefGoogle Scholar
  17. 17.
    Beiderbeck AB, Holly EA, Sturkenboom MC, Coebergh JW, Stricker BH, Leufkens HG (2003) Prescription medications associated with a decreased risk of non-Hodgkin’s lymphoma. Am J Epidemiol 157:510–516PubMedCrossRefGoogle Scholar
  18. 18.
    Holly EA, Lele C, Bracci PM, McGrath MS (1999) Case–control study of non-Hodgkin’s lymphoma among women and heterosexual men in the San Francisco Bay Area, California. Am J Epidemiol 150:375–389PubMedGoogle Scholar
  19. 19.
    Holly EA, Bracci PM (2003) Population-based study of non-Hodgkin lymphoma, histology, and medical history among human immunodeficiency virus-negative participants in San Francisco. Am J Epidemiol 158:316–327PubMedCrossRefGoogle Scholar
  20. 20.
    Baker JA, Weiss JR, Czuczman MS, Menezes RJ, Ambrosone CB, Moysich KB (2005) Regular use of aspirin or acetaminophen and risk of non-Hodgkin lymphoma. Cancer Causes Control 16:301–308PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L (2006) Risk of non-Hodgkin lymphoma and use of non-steroidal anti-inflammatory drugs. Cancer Detect Prev 30:99–101PubMedCrossRefGoogle Scholar
  22. 22.
    Chang ET, Zheng T, Weir EG et al (2004) Aspirin and the risk of Hodgkin’s lymphoma in a population-based case–control study. J Natl Cancer Inst 96:305–315PubMedCrossRefGoogle Scholar
  23. 23.
    Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr (1993) Aspirin use and risk of fatal cancer. Cancer Res 53:1322–1327PubMedGoogle Scholar
  24. 24.
    Ratnasinghe LD, Graubard BI, Kahle L, Tangrea JA, Taylor PR, Hawk E (2004) Aspirin use and mortality from cancer in a prospective cohort study. Anticancer Res 24:3177–3184PubMedGoogle Scholar
  25. 25.
    Roper RL, Phipps RP (1992) Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and IgG1 synthesis. J Immunol 149:2984–2991PubMedGoogle Scholar
  26. 26.
    Stein SH, Phipps RP (1992) Anti-class II antibodies potentiate IgG2a production by lipopolysaccharide-stimulated B lymphocytes treated with prostaglandin E2 and IFN-gamma. J Immunol 148:3943–3949PubMedGoogle Scholar
  27. 27.
    IARC (1997) Non-steroidal anti-inflammatory drugs. IARC, LyonGoogle Scholar
  28. 28.
    Goodwin JS, Messner RP, Bankhurst AD, Peake GT, Saiki JH, Williams RC Jr (1977) Prostaglandin-producing suppressor cells in Hodgkin’s disease. N Engl J Med 297:963–968PubMedCrossRefGoogle Scholar
  29. 29.
    Cayeux SJ, Beverley PC, Schulz R, Dorken B (1993) Elevated plasma prostaglandin E2 levels found in 14 patients undergoing autologous bone marrow or stem cell transplantation. Bone Marrow Transplant 12:603–608PubMedGoogle Scholar
  30. 30.
    Ladetto M, Vallet S, Trojan A et al (2005) Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Blood 105:4784–4791PubMedCrossRefGoogle Scholar
  31. 31.
    Hazar B, Ergin M, Seyrek E, Erdogan S, Tuncer I, Hakverdi S (2004) Cyclooxygenase-2 (Cox-2) expression in lymphomas. Leuk Lymphoma 45:1395–1399PubMedCrossRefGoogle Scholar
  32. 32.
    Li HL, Sun BZ, Ma FC (2004) Expression of COX-2, iNOS, p53 and Ki-67 in gastric mucosa-associated lymphoid tissue lymphoma. World J Gastroenterol 10:1862–1866PubMedGoogle Scholar
  33. 33.
    Paydas S, Ergin M, Erdogan S, Seydaoglu G (2007) Cyclooxygenase-2 expression in non-Hodgkin’s lymphomas. Leuk Lymphoma 48:389–395PubMedCrossRefGoogle Scholar
  34. 34.
    Wang D, DuBois RN (2006) Prostaglandins and cancer. Gut 55:115–122PubMedCrossRefGoogle Scholar
  35. 35.
    Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147PubMedGoogle Scholar
  36. 36.
    Dinarello CA, Thompson RC (1991) Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 12:404–410PubMedCrossRefGoogle Scholar
  37. 37.
    Reznikov LL, Kim SH, Westcott JY et al (2000) IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma. Proc Natl Acad Sci U S A 97:2174–2179PubMedCrossRefGoogle Scholar
  38. 38.
    Cipollone F, Patrono C (2002) Cyclooxygenase-2 polymorphism: putting a brake on the inflammatory response to vascular injury? Arterioscler Thromb Vasc Biol 22:1516–1518PubMedCrossRefGoogle Scholar
  39. 39.
    Arend WP (2002) The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 13:323–340PubMedCrossRefGoogle Scholar
  40. 40.
    Cox DG, Pontes C, Guino E et al (2004) Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 91:339–343PubMedGoogle Scholar
  41. 41.
    Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F (2004) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25:229–235PubMedCrossRefGoogle Scholar
  42. 42.
    Gallicchio L, McSorley MA, Newschaffer CJ et al (2006) Nonsteroidal antiinflammatory drugs, cyclooxygenase polymorphisms, and the risk of developing breast carcinoma among women with benign breast disease. Cancer 106:1443–1452PubMedCrossRefGoogle Scholar
  43. 43.
    Sakoda LC, Gao YT, Chen BE et al (2006) Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Carcinogenesis 27:1251–1256PubMedCrossRefGoogle Scholar
  44. 44.
    Gunter MJ, Canzian F, Landi S, Chanock SJ, Sinha R, Rothman N (2006) Inflammation-related gene polymorphisms and colorectal adenoma. Cancer Epidemiol Biomarkers Prev 15:1126–1131PubMedCrossRefGoogle Scholar
  45. 45.
    Ulrich CM, Whitton J, Yu JH et al (2005) PTGS2 (COX-2) -765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol Biomarkers Prev 14:616–619PubMedCrossRefGoogle Scholar
  46. 46.
    Siezen CL, van Leeuwen AI, Kram NR, Luken ME, van Kranen HJ, Kampman E (2005) Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption. Carcinogenesis 26:449–457PubMedCrossRefGoogle Scholar
  47. 47.
    Koh WP, Yuan JM, van den Berg D, Lee HP, Yu MC (2004) Interaction between cyclooxygenase-2 gene polymorphism and dietary n-6 polyunsaturated fatty acids on colon cancer risk: the Singapore Chinese Health Study. Br J Cancer 90:1760–1764PubMedGoogle Scholar
  48. 48.
    Hedelin M, Chang ET, Wiklund F et al (2007) Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism. Int J Cancer 120:398–405PubMedCrossRefGoogle Scholar
  49. 49.
    Lightfoot T, Skibola CF, Adamson P et al (2006) Polymorphisms in the oxidative stress genes, superoxide dismutase, glutathione peroxidase and catalase and risk of non-Hodgin lymphoma. Haematologica 91(9):1222–1227PubMedGoogle Scholar
  50. 50.
    Becker N, Deeg E, Nieters A (2004) Population-based study of lymphoma in Germany: rationale, study design and first results. Leuk Res 28:713–724PubMedCrossRefGoogle Scholar
  51. 51.
    Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434PubMedCrossRefGoogle Scholar
  52. 52.
    Lake SL, Lyon H, Tantisira K et al (2003) Estimation and tests of haplotype–environment interaction when linkage phase is ambiguous. Hum Hered 55:56–65PubMedCrossRefGoogle Scholar
  53. 53.
    Rothman N, Skibola CF, Wang SS et al (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7:27–38PubMedCrossRefGoogle Scholar
  54. 54.
    Endres S, Cannon JG, Ghorbani R et al (1989) In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol 19:2327–2333PubMedCrossRefGoogle Scholar
  55. 55.
    Thun MJ, Henley SJ, Patrono C (2002) Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94:252–266PubMedGoogle Scholar
  56. 56.
    Ferroni P, Martini F, Cardarello CM, Gazzaniga PP, Davi G, Basili S (2003) Enhanced interleukin-1beta in hypercholesterolemia: effects of simvastatin and low-dose aspirin. Circulation 108:1673–1675PubMedCrossRefGoogle Scholar
  57. 57.
    Daun JM, Ball RW, Burger HR, Cannon JG (1999) Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo. J Leukoc Biol 65:863–866PubMedGoogle Scholar
  58. 58.
    Tountas NA, Casini-Raggi V, Yang H et al (1999) Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis. Gastroenterology 117:806–813PubMedCrossRefGoogle Scholar
  59. 59.
    Tolusso B, Pietrapertosa D, Morelli A et al (2006) IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy. Pharmacogenomics 7:683–695PubMedCrossRefGoogle Scholar
  60. 60.
    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 47:195–198PubMedCrossRefGoogle Scholar
  61. 61.
    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 Immunol 28:2598–2602PubMedCrossRefGoogle Scholar
  62. 62.
    Vamvakopoulos J, Green C, Metcalfe S (2002) Genetic control of IL-1beta bioactivity through differential regulation of the IL-1 receptor antagonist. Eur J Immunol 32:2988–2996PubMedCrossRefGoogle Scholar
  63. 63.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  64. 64.
    Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14:433–439PubMedCrossRefGoogle Scholar
  65. 65.
    Skibola C, Curry JD, Nieters A (2007) Genetic susceptibility to lymphoma. Haematologica 92(7):960–969PubMedCrossRefGoogle Scholar
  66. 66.
    Zhu H, Liu C (2003) Interleukin-1 inhibits hepatitis C virus subgenomic RNA replication by activation of extracellular regulated kinase pathway. J Virol 77:5493–5498PubMedCrossRefGoogle Scholar
  67. 67.
    Witkin SS, Gerber S, Ledger WJ (2002) Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin Infect Dis 34:204–209PubMedCrossRefGoogle Scholar
  68. 68.
    Ouburg S, Bart AC, Klinkenberg-Knol EC, Mulder CJ, Salvador PA, Morre SA (2005) A candidate gene approach of immune mediators effecting the susceptibility to and severity of upper gastrointestinal tract diseases in relation to Helicobacter pylori and Epstein-Barr virus infections. Eur J Gastroenterol Hepatol 17:1213–1224PubMedCrossRefGoogle Scholar
  69. 69.
    Kim N, Cho SI, Yim JY et al (2006) The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea. Helicobacter 11:105–112PubMedCrossRefGoogle Scholar
  70. 70.
    Nieters A, Kallinowski B, Brennan P et al (2006) Hepatitis C and risk of lymphoma: results of the European multicenter case–control study EPILYMPH. Gastroenterology 131:1879–1886PubMedCrossRefGoogle Scholar
  71. 71.
    Rollinson S, Levene AP, Mensah FK et al (2003) Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity. Blood 102:1007–1011PubMedCrossRefGoogle Scholar
  72. 72.
    Wu MS, Shun CT, Huang SP, Cheng AL, Chen LT, Lin JT (2004) Effect of interleukin-1beta and glutathione S-transferase genotypes on the development of gastric mucosa-associated lymphoid tissue lymphoma. Haematologica 89:1015–1017PubMedGoogle Scholar
  73. 73.
    Rothman N, Skibola CF, Wang SS et al (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7:27–38PubMedCrossRefGoogle Scholar
  74. 74.
    Chang ET, Smedby KE, Hjalgrim H et al (2005) Medication use and risk of non-Hodgkin’s lymphoma. Am J Epidemiol 162:965–974PubMedCrossRefGoogle Scholar
  75. 75.
    Baker JA, Weiss JR, Czuczman MS, Menezes RJ, Ambrosone CB, Moysich KB (2005) Regular use of aspirin or acetaminophen and risk of non-Hodgkin lymphoma. Cancer Causes Control 16:301–308PubMedCrossRefGoogle Scholar
  76. 76.
    Franconi F, Brunelleschi S, Steardo L, Cuomo V (2007) Gender differences in drug responses. Pharmacol Res 55:81–95PubMedCrossRefGoogle Scholar
  77. 77.
    Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–59PubMedCrossRefGoogle Scholar
  78. 78.
    Jost PJ, Ruland J (2006) Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences and therapeutic implications. Blood 109(7):2700–2707Google Scholar
  79. 79.
    Kato I, Koenig KL, Baptiste MS et al (2003) History of antibiotic use and risk of non-Hodgkin’s lymphoma (NHL). Int J Cancer 107:99–105PubMedCrossRefGoogle Scholar
  80. 80.
    Doody MM, Linet MS, Glass AG et al (1996) Risks of non-Hodgkin’s lymphoma, multiple myeloma, and leukemia associated with common medications. Epidemiology 7:131–139PubMedCrossRefGoogle Scholar
  81. 81.
    Beiderbeck AB, Holly EA, Sturkenboom MC, Coebergh JW, Stricker BH, Leufkens HG (2003) Prescription medications associated with a decreased risk of non-Hodgkin’s lymphoma. Am J Epidemiol 157:510–516PubMedCrossRefGoogle Scholar
  82. 82.
    Cerhan JR, Wallace RB, Folsom AR et al (1997) Medical history risk factors for non-Hodgkin’s lymphoma in older women. J Natl Cancer Inst 89:314–318PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Birgit Hoeft
    • 1
  • Nikolaus Becker
    • 2
  • Evelin Deeg
    • 2
  • Lars Beckmann
    • 3
  • Alexandra Nieters
    • 1
  1. 1.Molecular Tumour Epidemiology, Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  2. 2.Fundaments of Cancer Prevention, Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Genetic Epidemiology, Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany

Personalised recommendations