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Infectious Medicine

Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia

Abstract

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at –174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.

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References

  1. Madani TA . Clinical infections and bloodstream isolates associated with fever in patients undergoing chemotherapy for acute myeloid leukemia. Infection 2000; 28: 367–373.

    Article  CAS  Google Scholar 

  2. Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Klingebiel T, Creutzig U . Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 2004; 18: 72–77.

    Article  CAS  Google Scholar 

  3. Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T . Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol 2004; 22: 4384–4393.

    Article  Google Scholar 

  4. Riley LC, Hann IM, Wheatley K, Stevens RF . Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council acute myeloid leukaemia trial (MRC AML10). The MCR Childhood Leukaemia Working Party. Br J Haematol 1999; 106: 436–444.

    Article  CAS  Google Scholar 

  5. Tunkel AR, Sepkowitz KA . Infections caused by viridans streptococci in patients with neutropenia. Clin Infect Dis 2002; 34: 1524–1529.

    Article  Google Scholar 

  6. Taylor JG, Choi EH, Foster CB, Chanock SJ . Using genetic variation to study human disease. Trends Mol Med 2001; 7: 507–512.

    Article  CAS  Google Scholar 

  7. Chanock S . Candidate genes and single nucleotide polymorphisms (SNPs) in the study of human disease. Dis Markers 2001; 17: 89–98.

    Article  CAS  Google Scholar 

  8. Foster CB, Chanock SJ . Mining variations in genes of innate and phagocytic immunity: current status and future prospects. Curr Opin Hematol 2000; 7: 9–15.

    Article  CAS  Google Scholar 

  9. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.

    Article  CAS  Google Scholar 

  10. Lehrnbecher T, Foster CB, Zhu S, Venzon D, Steinberg SM, Wyvill K et al. Variant genotypes of FcgammaRIIIA influence the development of Kaposi's sarcoma in HIV-infected men. Blood 2000; 95: 2386–2390.

    CAS  PubMed  Google Scholar 

  11. Choi EH, Foster CB, Taylor JG, Erichsen HC, Chen RA, Walsh TJ et al. Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J Infect Dis 2003; 187: 1153–1156.

    Article  CAS  Google Scholar 

  12. Stuber F, Petersen M, Bokelmann F, Schade U . A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis [see comments]. Crit Care Med 1996; 24: 381–384.

    Article  CAS  Google Scholar 

  13. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

    Article  CAS  Google Scholar 

  14. Harding D, Dhamrait S, Millar A, Humphries S, Marlow N, Whitelaw A et al. Is interleukin-6 −174 genotype associated with the development of septicemia in preterm infants? Pediatrics 2003; 112: 800–803.

    Article  Google Scholar 

  15. Jiang ZD, Okhuysen PC, Guo DC, He R, King TM, DuPont HL et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis 2003; 188: 506–511.

    Article  CAS  Google Scholar 

  16. Rocha V, Franco RF, Porcher R, Bittencourt H, Silva Jr WA, Latouche A et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 100: 3908–3918.

    Article  CAS  Google Scholar 

  17. Choi EH, Zimmerman PA, Foster CB, Zhu S, Kumaraswami V, Nutman TB et al. Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India. Genes Immun 2001; 2: 248–253.

    Article  CAS  Google Scholar 

  18. Norris CF, Surrey S, Bunin GR, Schwartz E, Buchanan GR, McKenzie SE . Relationship between Fc receptor IIA polymorphism and infection in children with sickle cell disease. J Pediatr 1996; 128: 813–819.

    Article  CAS  Google Scholar 

  19. Foster CB, Lehrnbecher T, Mol F, Steinberg SM, Venzon DJ, Walsh TJ et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest 1998; 102: 2146–2155.

    Article  CAS  Google Scholar 

  20. Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J Infect Dis 2002; 186: 1522–1525.

    Article  CAS  Google Scholar 

  21. Meier A, Kirschning CJ, Nikolaus T, Wagner H, Heesemann J, Ebel F . Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol 2003; 5: 561–570.

    Article  CAS  Google Scholar 

  22. Creutzig U, Ritter J, Zimmermann M, Reinhardt D, Hermann J, Berthold F et al. Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin–Frankfurt–Munster 93. J Clin Oncol 2001; 19: 2705–2713.

    Article  CAS  Google Scholar 

  23. Lehrnbecher T, Fleischhack G, Hanisch M, Deinlein F, Simon A, Bernig T et al. Circulating levels and promoter polymorphisms of interleukin-6 and 8 in pediatric cancer patients with fever and neutropenia. Haematologica 2004; 89: 234–236.

    CAS  PubMed  Google Scholar 

  24. Schroder NW, Hermann C, Hamann L, Gobel UB, Hartung T, Schumann RR . High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR. J Mol Med 2003; 81: 368–372.

    Article  Google Scholar 

  25. Packer BR, Yeager M, Staats B, Welch R, Crenshaw A, Kiley M et al. SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes. Nucleic Acids Res 2004; 32 (Database issue): D528–D532.

    Article  CAS  Google Scholar 

  26. Boot RG, Renkema GH, Verhoek M, Strijland A, Bliek J, de Meulemeester TM et al. The human chitotriosidase gene nature of inherited enzyme deficiency. J Biol Chem 1998; 273: 25680–25685.

    Article  CAS  Google Scholar 

  27. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA . A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 2000; 68: 6398–6401.

    Article  CAS  Google Scholar 

  28. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N . Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 2004; 96: 434–442.

    Article  Google Scholar 

  29. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995; 57: 289–300.

    Google Scholar 

  30. Kalbfleisch JD, Prentice RL . The Statistical Analysis of Failure Time Data. John Wiley: New York, 1980, 163–188.

    Google Scholar 

  31. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  32. Schluter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S et al. Effect of the interleukin-6 promoter polymorphism (−174 G/C) on the incidence and outcome of sepsis. Crit Care Med 2002; 30: 32–37.

    Article  CAS  Google Scholar 

  33. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  34. Stram DO, Haiman CA, Hirschhorn JN, Altshuler D, Kolonel LN, Henderson BE et al. Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 2003; 55: 27–36.

    Article  Google Scholar 

  35. Wacholder S, Rothman N, Caporaso N . Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst 2000; 92: 1151–1158.

    Article  CAS  Google Scholar 

  36. Lehrnbecher T, Foster C, Vazquez N, Mackall CL, Chanock SJ . Therapy-induced alterations in host defense in children receiving chemotherapy. J Ped Hematol Oncol 1997; 19: 399–417.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Martin Zimmermann for his excellent advice for the statistical analysis. The study was supported by the Deutsche Krebshilfe.

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Correspondence to T Lehrnbecher.

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Lehrnbecher, T., Bernig, T., Hanisch, M. et al. Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia. Leukemia 19, 1745–1750 (2005). https://doi.org/10.1038/sj.leu.2403922

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