Skip to main content
SpringerLink
Log in

Impact of cytokine gene polymorphisms on risk and treatment outcomes of aplastic anemia

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Autoreactive cytotoxic T cells play a key role in the pathogenesis of aplastic anemia (AA) by myelosuppressive cytokines including interferon-gamma, tumor necrosis factor alpha, and transforming growth factor beta. The purpose of this study is to determine which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to AA risk and whether the relevant SNPs were associated with response to immunosuppressive therapy (IST). Among 84 screened patients, 80 patients confirmed as having acquired AA, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped ten polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene. We assessed the association between polymorphisms and AA risk, and the association between polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG −2,353 T allele (dominant model, OR = 0.43, p = .012) and TCA haplotype (dominant model, OR = 0.50, p = .038) were significantly associated with the development of AA. In addition, this relevant IFNG −2,353 T allele and TCA haplotype were related to the response of IST (dominant model, OR = 0.076, p = .034). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, OR = 0.18, p = .038) and CT haplotype (dominant model, OR = 5.68, p = .038) were associated with response to IST. This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST.

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

Fig. 1

Similar content being viewed by others

References

  1. Young N, Calado R, Scheinberg P (2006) Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108:2509

    Article  PubMed  CAS  Google Scholar 

  2. Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F, Gabbas A, Dufour C, Arcese W, Testi G, Broccia G, Carotenuto M, Coser P, Barbui T, Leoni P, Ferster A (2000) Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood 95:1931–1934

    PubMed  CAS  Google Scholar 

  3. Fuhrer M, Rampf U, Baumann I, Faldum A, Niemeyer C, Janka-Schaub G, Friedrich W, Ebell W, Borkhardt A, Bender-Goetze C (2005) Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood 106:2102–2104

    Article  PubMed  Google Scholar 

  4. Locasciulli A, Oneto R, Bacigalupo A, Socie G, Korthof E, Bekassy A, Schrezenmeier H, Passweg J, Fuhrer M (2007) Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood to Marrow Transplantation (EBMT). Haematologica 92:11–18

    Article  PubMed  CAS  Google Scholar 

  5. Dufour C, Corcione A, Svahn J, Haupt R, Battilana N, Pistoia V (2001) Interferon gamma and tumour necrosis factor alpha are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia. Br J Haematol 115:1023–1031

    Article  PubMed  CAS  Google Scholar 

  6. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS (2002) Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood 100:1185–1191

    Article  PubMed  CAS  Google Scholar 

  7. Maciejewski J, Selleri C, Anderson S, Young NS (1995) Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 85:3183–3190

    PubMed  CAS  Google Scholar 

  8. Killick SB, Cox CV, Marsh JC, Gordon-Smith EC, Gibson FM (2000) Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin: examination of the role of the Fas-Fas-L interaction. Br J Haematol 111:1164–1169

    Article  PubMed  CAS  Google Scholar 

  9. Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134:392–404

    Article  PubMed  CAS  Google Scholar 

  10. Rizzo S, Killick SB, Patel S, Ball SE, Wadhwa M, Dilger P, Gordon-Smith EC, Gibson FM (1999) Reduced TGF-beta1 in patients with aplastic anaemia in vivo and in vitro. Br J Haematol 107:797–803

    Article  PubMed  CAS  Google Scholar 

  11. Dufour C, Capasso M, Svahn J, Marrone A, Haupt R, Bacigalupo A, Giordani L, Longoni D, Pillon M, Pistorio A, Di Michele P, Iori AP, Pongiglione C, Lanciotti M, Iolascon A (2004) Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol 126:682–685

    Article  PubMed  CAS  Google Scholar 

  12. Gidvani V, Ramkissoon S, Sloand EM, Young NS (2007) Cytokine gene polymorphisms in acquired bone marrow failure. Am J Hematol 82:721–724

    Article  PubMed  CAS  Google Scholar 

  13. Peng J, Liu C, Zhu K, Zhu Y, Yu Y, Li J, Hou M, Chen X, Xu C, Zhang M (2003) The TNF2 allele is a risk factor to severe aplastic anemia independent of HLA-DR. Hum Immunol 64:896–901

    Article  PubMed  CAS  Google Scholar 

  14. Demeter J, Messer G, Schrezenmeier H (2002) Clinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients with aplastic anemia. Ann Hematol 81:566–569

    Article  PubMed  CAS  Google Scholar 

  15. Takaku T, Calado RT, Kajigaya S, Young NS (2009) Interleukin-23 receptor (IL-23R) gene polymorphisms in acquired aplastic anemia. Ann Hematol 88:653–657

    Article  PubMed  CAS  Google Scholar 

  16. Anonymous (1987) Incidence of aplastic anemia: the relevance of diagnostic criteria. By the international agranulocytosis and aplastic anemia study. Blood 70:1718–1721

    Google Scholar 

  17. Camitta B, Thomas E, Nathan D, Santos G, Gordon-Smith E, Gale R, Rappeport J, Storb R (1976) Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 48:63

    PubMed  CAS  Google Scholar 

  18. Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint M, Congiu M, De Planque M, Ernst P, McCann S (1988) Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT* SAA Working Party. Br J Haematol 70:177–182

    Article  PubMed  CAS  Google Scholar 

  19. Camitta BM (2000) What is the definition of cure for aplastic anemia? Acta Haematol 103:16–18

    Article  PubMed  CAS  Google Scholar 

  20. Scheinberg P, Wu CO, Nunez O, Young NS (2009) Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 144:206–216

    Article  PubMed  CAS  Google Scholar 

  21. Nistico A, Young NS (1994) Gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 120:463–469

    PubMed  CAS  Google Scholar 

  22. Pravica V, Asderakis A, Perrey C, Hajeer A, Sinnott PJ, Hutchinson IV (1999) In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 26:1–3

    Article  PubMed  CAS  Google Scholar 

  23. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV (2000) A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61:863–866

    Article  PubMed  CAS  Google Scholar 

  24. Fermo E, Bianchi P, Barcellini W, Pedotti P, Boschetti C, Alfinito F, Cortelezzi A, Zanella A (2004) Immunoregulatory cytokine polymorphisms in Italian patients affected by paroxysmal nocturnal haemoglobinuria and aplastic anaemia. Eur J Immunogenet 31:267–269

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by grant title “The impact of genetic polymorphism on the prevalance and treatment outcomes of aplastic anemia” from the Korea Cancer Research Foundation and by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (0405-BC02-0604-0004).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea

    Yun-Gyoo Lee, Inho Kim, Ji-Hyun Kwon, Dong-Yeop Shin, Sung-Soo Yoon, Seonyang Park & Byoung Kook Kim

  2. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Jin Hee Kim & Yun-Chul Hong

  3. Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea

    Eun Young Song, Hyun Kyoung Kim, Sung Sup Park, Dong Soon Lee, Kyou-Sup Han & Myoung Hee Park

  4. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Inho Kim, Ji-Yeon Bae, Sung-Soo Yoon, Seonyang Park & Byoung Kook Kim

  5. Diagnostic DNA chip Center, Seoul National University College of Medicine, Seoul, South Korea

    Inho Kim & Seonyang Park

  6. Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, South Korea

    Jin Hee Kim & Yun-Chul Hong

  7. DNA Link Inc, Seoul, South Korea

    Jong-Eun Lee

Authors
  1. Yun-Gyoo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Hee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ji-Yeon Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji-Hyun Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong-Yeop Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong-Eun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eun Young Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hyun Kyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sung-Soo Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sung Sup Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dong Soon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kyou-Sup Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Myoung Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yun-Chul Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Seonyang Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Byoung Kook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Inho Kim.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table 1

Primer sets and Tm for the SNaPshot assay. (DOC 76 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, YG., Kim, I., Kim, J.H. et al. Impact of cytokine gene polymorphisms on risk and treatment outcomes of aplastic anemia. Ann Hematol 90, 515–521 (2011). https://doi.org/10.1007/s00277-010-1102-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-010-1102-2

Keywords

Search

Navigation