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.

  • Review
  • Published:

Genomic studies of GVHD—lessons learned thus far

Bone Marrow Transplantation volume 48, pages 4–9 (2013)Cite this article

Subjects

Abstract

GVHD remains the most significant complication of hematopoietic SCT, despite advances in HLA matching and the identification of risk various factors. To account for the variation in the incidence and severity of this disease, many genetic association studies have been performed in order to explore the role of immunoregulatory gene polymorphisms. These genes include those that encode cytokines, chemokines, and costimulatory molecules. Polymorphisms in other classes of genes such as those involved in drug metabolism, protein folding, and DNA replication have also been studied. In this review, we address the current knowledge of the role of genetic polymorphisms in GVHD. We also discuss the potential pitfalls inherent in genetic association testing and alternative strategies to address these problems.

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

Similar content being viewed by others

References

  1. Conway SE, Abdi R . Immunoregulatory gene polymorphisms and graft-versus-host disease. Expert Rev Clin Immunol 2009; 5: 523–534.

    Article  CAS  PubMed  Google Scholar 

  2. Shaw BE, Arguello R, Garcia-Sepulveda CA, Madrigal JA . The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation. Br J Haematol 2010; 150: 251–258.

    Article  PubMed  Google Scholar 

  3. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  PubMed  Google Scholar 

  4. Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Horwitz ME, Sullivan KM . Chronic graft-versus-host disease. Blood Rev 2006; 20: 15–27.

    Article  PubMed  Google Scholar 

  6. Socie G . Chronic GVHD: B cells come of age. Blood 2011; 117: 2086–2087.

    Article  CAS  PubMed  Google Scholar 

  7. Socie G, Ritz J, Martin PJ . Current challenges in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16 (1 Suppl): S146–S151.

    Article  PubMed  Google Scholar 

  8. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Petersdorf EW, Pereira SE et al. Comparative analysis of risk factors for acute and for chronic graft-versus-host-disease according to National Institute of Health consensus criteria. Blood 2011; 117: 3214–3219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hansen JA, Chien JW, Warren EH, Zhao LP, Martin PJ . Defining genetic risk for graft-versus-host disease and mortality following allogeneic hematopoietic stem cell transplantation. Curr Opin Hematol 2010; 17: 483–492.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K et al. Biology of interleukin-10. Cytokine Growth Factor Rev 2010; 21: 331–344.

    Article  CAS  PubMed  Google Scholar 

  11. McDermott DH, Conway SE, Wang T, Ricklefs SM, Agovi MA, Porcella SF et al. Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation. Blood 2010; 115: 2311–2318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506–511.

    Article  CAS  PubMed  Google Scholar 

  13. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6: 435–442.

    Article  CAS  PubMed  Google Scholar 

  14. Bogunia-Kubik K, Koscinska K, Suchnicki K, Lange A . HSP70-hom gene single nucleotide (+2763 G/A and +2437 C/T) polymorphisms in sarcoidosis. Int J Immunogenet 2006; 33: 135–140.

    Article  CAS  PubMed  Google Scholar 

  15. Ostrovsky O, Shimoni A, Rand A, Vlodavsky I, Nagler A . Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors. Blood 2010; 115: 2319–2328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Holler E, Rogler G, Brenmoehl J, Hahn J, Greinix H, Dickinson AM et al. The role of genetic variants of NOD2/CARD15, a receptor of the innate immune system, in GvHD and complications following related and unrelated donor haematopoietic stem cell transplantation. Int J Immunogenet 2008; 35: 381–384.

    Article  CAS  PubMed  Google Scholar 

  17. Elmaagacli AH, Koldehoff M, Hindahl H, Steckel NK, Trenschel R, Peceny R et al. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation 2006; 81: 247–254.

    Article  CAS  PubMed  Google Scholar 

  18. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE . Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001; 22: 195–201.

    Article  CAS  PubMed  Google Scholar 

  19. Robien K, Bigler J, Yasui Y, Potter JD, Martin P, Storb R et al. Methylenetetrahydrofolate reductase and thymidylate synthase genotypes and risk of acute graft-versus-host disease following hematopoietic cell transplantation for chronic myelogenous leukemia. Biol Blood Marrow Transplant 2006; 12: 973–980.

    Article  CAS  PubMed  Google Scholar 

  20. Kaneda S, Takeishi K, Ayusawa D, Shimizu K, Seno T, Altman S . Role in translation of a triple tandemly repeated sequence in the 5′-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 1987; 15: 1259–1270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF et al. Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 1999; 1: 3–19.

    Article  CAS  PubMed  Google Scholar 

  22. Bacchetta R, Bigler M, Touraine JL, Parkman R, Tovo PA, Abrams J et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994; 179: 493–502.

    Article  CAS  PubMed  Google Scholar 

  23. 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  PubMed  Google Scholar 

  24. Lin MT, Storer B, Martin PJ, Tseng LH, Grogan B, Chen PJ et al. Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor beta genotype of donor. Blood 2005; 106: 3995–4001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Murai M, Yoneyama H, Harada A, Yi Z, Vestergaard C, Guo B et al. Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest 1999; 104: 49–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tseng LH, Storer B, Petersdorf E, Lin MT, Chien JW, Grogan BM et al. IL10 and IL10 receptor gene variation and outcomes after unrelated and related hematopoietic cell transplantation. Transplantation 2009; 87: 704–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sivula J, Turpeinen H, Volin L, Partanen J . Association of IL-10 and IL-10Rbeta gene polymorphisms with graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling donor. BMC Immunol 2009; 10: 24.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Perez-Garcia A, De la Camara R, Roman-Gomez J, Jimenez-Velasco A, Encuentra M, Nieto JB et al. CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors. Blood 2007; 110: 461–467.

    Article  CAS  PubMed  Google Scholar 

  29. Nguyen Y, Al-Lehibi A, Gorbe E, Li E, Haagenson M, Wang T et al. Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease-associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation. Blood 2010; 115: 3625–3631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Robien K, Schubert MM, Chay T, Bigler J, Storb R, Yasui Y et al. Methylenetetrahydrofolate reductase and thymidylate synthase genotypes modify oral mucositis severity following hematopoietic stem cell transplantation. Bone Marrow Transplant 2006; 37: 799–800.

    Article  CAS  PubMed  Google Scholar 

  31. Mehta PA, Eapen M, Klein JP, Gandham S, Elliott J, Zamzow T et al. Interleukin-1 alpha genotype and outcome of unrelated donor haematopoietic stem cell transplantation for chronic myeloid leukaemia. Br J Haematol 2007; 137: 152–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Elmaagacli AH, Koldehoff M, Landt O, Beelen DW . Relation of an interleukin-23 receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation. Bone Marrow Transplant 2008; 41: 821–826.

    Article  CAS  PubMed  Google Scholar 

  33. Arora M, Lindgren B, Basu S, Nagaraj S, Gross M, Weisdorf D et al. Polymorphisms in the base excision repair pathway and graft-versus-host disease. Leukemia 2010; 24: 1470–1475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gupta G, Womer KL . Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation. Drug Des Devel Ther 2010; 4: 375–382.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Goral J, Mathews HL, Nadler SG, Clancy J . Reduced levels of Hsp70 result in a therapeutic effect of 15-deoxyspergualin on acute graft-versus-host disease in (DA x LEW)F1 rats. Immunobiology 2000; 202: 254–266.

    Article  CAS  PubMed  Google Scholar 

  36. Goral J, Shenoy S, Mohanakumar T, Clancy Jr J . Antibodies to 70 kD and 90 kD heat shock proteins are associated with graft-versus-host disease in peripheral blood stem cell transplant recipients. Clin Exp Immunol 2002; 127: 553–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bogunia-Kubik K, Lange A . HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease. Transplantation 2005; 79: 815–820.

    Article  CAS  PubMed  Google Scholar 

  38. Bogunia-Kubik K, Uklejewska A, Dickinson A, Jarvis M, Lange A . HSP70-hom gene polymorphism as a prognostic marker of graft-versus-host disease. Transplantation 2006; 82: 1116–1117.

    Article  PubMed  Google Scholar 

  39. Parish CR, Freeman C, Hulett MD . Heparanase: a key enzyme involved in cell invasion. Biochim Biophys Acta 2001; 1471: M99–108.

    CAS  PubMed  Google Scholar 

  40. Vlodavsky I, Eldor A, Haimovitz-Friedman A, Matzner Y, Ishai-Michaeli R, Lider O et al. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 1992; 12: 112–127.

    CAS  PubMed  Google Scholar 

  41. Ilan N, Elkin M, Vlodavsky I . Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol 2006; 38: 2018–2039.

    Article  CAS  PubMed  Google Scholar 

  42. McKenzie EA . Heparanase: a target for drug discovery in cancer and inflammation. Br J Pharmacol 2007; 151: 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F et al. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 2002; 277: 41701–41705.

    Article  CAS  PubMed  Google Scholar 

  44. Rocha V, Porcher R, Fernandes JF, Filion A, Bittencourt H, Silva Jr W et al. Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia 2009; 23: 545–556.

    Article  CAS  PubMed  Google Scholar 

  45. Murphy N, Diviney M, Szer J, Bardy P, Grigg A, Hoyt R et al. Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant 2006; 37: 773–779.

    Article  CAS  PubMed  Google Scholar 

  46. Sugimoto K, Murata M, Onizuka M, Inamoto Y, Terakura S, Kuwatsuka Y et al. Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype. Int J Hematol 2008; 87: 451–458.

    Article  CAS  PubMed  Google Scholar 

  47. Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6: 95–108.

    Article  CAS  PubMed  Google Scholar 

  48. Manolio TA, Collins FS . The HapMap and genome-wide association studies in diagnosis and therapy. Annu Rev Med 2009; 60: 443–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kamei M, Nannya Y, Torikai H, Kawase T, Taura K, Inamoto Y et al. HapMap scanning of novel human minor histocompatibility antigens. Blood 2009; 113: 5041–5048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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  PubMed  PubMed Central  Google Scholar 

  51. Murata M, Warren EH, Riddell SR . A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J Exp Med 2003; 197: 1279–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Terakura S, Murata M, Warren EH, Sette A, Sidney J, Naoe T et al. A single minor histocompatibility antigen encoded by UGT2B17 and presented by human leukocyte antigen-A*2902 and -B*4403. Transplantation 2007; 83: 1242–1248.

    Article  CAS  PubMed  Google Scholar 

  53. Chien JW, Zhao LP, Storer B, Martin PJ, Boeckh M, Warren EH et al. Improving hematopoietic cell transplant outcomes in a new era of genomic research. Biol Blood Marrow Transplant 2009; 15 (1 Suppl): 42–45.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Renal Division, Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, MA, USA

    C Ting & R Abdi

  2. Children's Hospital Informatics Program, Boston, MA, USA

    G Alterovitz & A Merlob

Authors
  1. C Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Alterovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Merlob
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to C Ting or R Abdi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ting, C., Alterovitz, G., Merlob, A. et al. Genomic studies of GVHD—lessons learned thus far. Bone Marrow Transplant 48, 4–9 (2013). https://doi.org/10.1038/bmt.2012.9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.9

Keywords

This article is cited by

Search

Advanced search

Quick links