Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genomics, Gene Therapy and Proteomics

Polymorphisms in the base excision repair pathway and graft-versus-host disease

Leukemia volume 24, pages 1470–1475 (2010)Cite this article

Subjects

Abstract

Graft-versus-host disease (GVHD) is a frequent complication after hematopoietic cell transplant (HCT). Tissue damage as a result of chemoradiation injury is the initiating event in the pathogenesis of acute GVHD. Variations in DNA repair can influence the amount of tissue damage in response to alkylating agents and ionizing radiation used as conditioning during HCT. As DNA damage caused by these agents is repaired by the base excision repair (BER) pathway, we hypothesized that single-nucleotide polymorphisms (SNPs) in BER pathway will be associated with GVHD after HCT. Hence, we analyzed 179 SNPs in BER pathway in 470 recipients of allogeneic HCT for association with acute and chronic GVHD. In multivariate analysis, one SNP (rs6844176) in RFC1 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II–IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14–1.70, P=0.001), and showed a trend toward higher risk of grade III–IV acute GVHD (RR: 1.33, 95% CI: 0.95–1.85, P=0.09). One SNP in PARP1 gene (rs1805410) was associated with a higher risk of chronic GVHD (RR: 1.81, 95% CI: 1.29–2.54, P=0.001). These results show that SNPs in the BER pathway can be used as genetic biomarkers to predict those at high risk for GVHD toward whom novel prophylactic strategies could be targeted.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Socie G, Blazar BR . Acute graft-versus-host disease; from the bench to the bedside. Blood 2009; 114: 4327–4336.

    Article  CAS  Google Scholar 

  2. Martin PJ . Biology of chronic graft-versus-host disease: implications for a future therapeutic approach. Keio J Med 2008; 57: 177–183.

    Article  Google Scholar 

  3. Lieberman HB . DNA damage repair and response proteins as targets for cancer therapy. Curr Med Chem 2008; 15: 360–367.

    Article  CAS  Google Scholar 

  4. Thyagarajan B, Lindgren B, Basu S, Nagaraj S, Gross M, Weisdorf D et al. Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplant. Biol Blood Marrow Transplant 2010, (e-pub ahead of print).

  5. Weisdorf D, Spellman S, Haagenson M, Horowitz M, Lee S, Anasetti C et al. Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival. Biol Blood Marrow Transplant 2008; 14: 748–758.

    Article  Google Scholar 

  6. NIEHSSNPs. NIEHS Environmental Genome Project, University of Washington, Seattle, WA (URL: http://www.egp.gs.washington.edu); January 2008.

  7. Ramensky V, Bork P, Sunyaev S . Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002; 30: 3894–3900.

    Article  CAS  Google Scholar 

  8. Ng PC, Henikoff S . Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002; 12: 436–446.

    Article  CAS  Google Scholar 

  9. Yue P, Melamud E, Moult J . SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 2006; 7: 166.

    Article  Google Scholar 

  10. RD Core Team. R: A Language and Environment for Statistical Computing. Foundation for Statistical Computing: Vienna, Austria, 2008.

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

    Article  CAS  Google Scholar 

  12. Fine J, Gray R . A proportional hazards model for the sub distribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  13. Jagtap P, Szabo C . Poly (ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Dis 2005; 4: 421–440.

    Article  CAS  Google Scholar 

  14. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB . Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 2004; 18: 1272–1282.

    Article  CAS  Google Scholar 

  15. Edinger AL, Thompson CB . Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004; 16: 663–669.

    Article  CAS  Google Scholar 

  16. Berger NA, Berger SJ . Metabolic consequences of DNA damage: the role of poly (ADP-ribose) polymerase as mediator of the suicide response. Basic Life Sci 1986; 38: 357–363.

    Article  CAS  Google Scholar 

  17. Ha HC, Snyder SH . Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 1999; 96: 13978–13982.

    Article  CAS  Google Scholar 

  18. Virag L, Szabo C . The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002; 54: 375–429.

    Article  CAS  Google Scholar 

  19. Chiarugi A . Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 2002; 23: 122–129.

    Article  CAS  Google Scholar 

  20. Hassa PO, Hottiger MO . A role of poly (ADP-ribose) polymerase in NF-κB transcriptional activation. Biol Chem 1999; 380: 953–959.

    Article  CAS  Google Scholar 

  21. McCarroll SA, Bradner JE, Turpeinen H, Volin L, Martin PJ, Chilewski SD et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet 2009; 41: 1341–1344.

    Article  CAS  Google Scholar 

  22. Bleakley MR, Riddell SR . Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer 2004; 4: 371–380.

    Article  CAS  Google Scholar 

  23. Goulmy E, Schipper R, Pool J, Blockland E, Falkenburg JH, Vossen J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–285.

    Article  CAS  Google Scholar 

  24. Tseng LH, Lin MT, Hansen JA, Gooley T, Pei J, Smith AG et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood 1999; 94: 2911–2914.

    CAS  PubMed  Google Scholar 

  25. Gallardo D, Arostegui JI, Balas A, Torres A, Caballero D, Carreras E et al. Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigenidentical sibling donor transplantation. Br J Haematol 2001; 114: 931–936.

    Article  CAS  Google Scholar 

  26. Socie G, Loiseau P, Tamouza R, Janin A, Busson N, Gluckman E et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 2001; 72: 699–706.

    Article  CAS  Google Scholar 

  27. Nesci S, Buffi O, Iliescu A, Andreani M, Lucarelli G . Recipient mHag-HA1 disparity and aGVHD in thalassemic-transplanted patients. Bone Marrow Transplant 2003; 31: 575–578.

    Article  CAS  Google Scholar 

  28. Tait BD, Maddison R, McCluskey J, Deayton S, Heatley S, Lester S et al. Clinical relevance of the minor histocompatibility antigen HA-1 in allogeneic bone marrow transplantation between HLA identical siblings. Transplant Proc 2001; 33: 1760–1761.

    Article  CAS  Google Scholar 

  29. Miklos DB, Kim HT, Zorn E, Hochberg EP, Guo L, Mattes-Ritz A et al. Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors. Blood 2004; 103: 353–359.

    Article  CAS  Google Scholar 

  30. Zorn E, Miklos DB, Floyd BH, Mattes-Ritz A, Guo L, Soiffer RJ et al. Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J Exp Med 2004; 199: 1133–1142.

    Article  CAS  Google Scholar 

  31. Nishida T, Akatsuka Y, Morishima Y, Hamajima N, Tsujimura K, Kuzushima K et al. Clinical relevance of a newly identified HLA-A24-restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC-1, in patients receiving HLA genotypically matched unrelated bone marrow transplant. Br J Haematol 2004; 124: 629–635.

    Article  CAS  Google Scholar 

  32. Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–2747.

    Article  CAS  Google Scholar 

  33. Antin JH, Ferrara JL . Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80: 2964–2968.

    CAS  Google Scholar 

  34. Cavet J, Middleton PG, Segall M, Noreen H, Davies SM, Dickinson AM . Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants. Blood 1999; 94: 3941–32946.

    CAS  PubMed  Google Scholar 

  35. Lin MT, Storer B, Martin PJ, Tseng LH, Gooley T, Chen PJ et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 2003; 349: 2201–2210.

    Article  CAS  Google Scholar 

  36. Dickinson AM, Charron D . Non-HLA immunogenetics in hematopoietic stem cell transplantation. Curr Opin Immunol 2005; 17: 517–525.

    Article  CAS  Google Scholar 

  37. Holler E, Rogler G, Brenmoehl J, Hahn J, Herfarth H, Greinix H et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 2006; 107: 4189–4193.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIAID (R21 AI079354-01) and the Leukemia Research Fund, University of Minnesota.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    M Arora, S Nagaraj & D Weisdorf

  2. Biostatistics and Informatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    B Lindgren

  3. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    S Basu

  4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    M Gross & B Thyagarajan

Authors
  1. M Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Lindgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Nagaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Weisdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Thyagarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Arora.

Ethics declarations

Competing interests

Dr Mukta Arora has received funding from the Leukemia Research Fund, University of Minnesota; and from NIAID for this project. Dr Bharat Thyagarajan has received funding from NIAID; the other co-authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arora, M., Lindgren, B., Basu, S. et al. Polymorphisms in the base excision repair pathway and graft-versus-host disease. Leukemia 24, 1470–1475 (2010). https://doi.org/10.1038/leu.2010.139

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.139

Keywords

This article is cited by

Search

Advanced search

Quick links