Biology of Blood and Marrow Transplantation
Volume 16, Issue 2 , Pages 239-252, February 2010

Association of HMGB1 Polymorphisms with Outcome after Allogeneic Hematopoietic Cell Transplantation

  • Brian Kornblit

      Affiliations

    • Laboratory of Molecular Medicine, Department of Clinical Immunology University of Copenhagen, Denmark
    • The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark
    • Corresponding Author InformationCorrespondence and reprint requests: Brian Kornblit, MD, The Allogeneic Hematopoietic Cell Transplantation Laboratory, 4041, Department of Hematology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark.
    • ,
  • Tania Masmas

      Affiliations

    • The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark
    • ,
  • Søren L. Petersen

      Affiliations

    • The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark
    • ,
  • Hans O. Madsen

      Affiliations

    • Laboratory of Molecular Medicine, Department of Clinical Immunology University of Copenhagen, Denmark
    • ,
  • Carsten Heilmann

      Affiliations

    • Pediatric Clinic II, Rigshospitalet, University of Copenhagen, Denmark
    • ,
  • Lone Schejbel

      Affiliations

    • Laboratory of Molecular Medicine, Department of Clinical Immunology University of Copenhagen, Denmark
    • ,
  • Henrik Sengeløv

      Affiliations

    • The Bone Marrow Transplantation Unit, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark
    • ,
  • Klaus Müller

      Affiliations

    • Pediatric Clinic II, Rigshospitalet, University of Copenhagen, Denmark
    • ,
  • Peter Garred

      Affiliations

    • Laboratory of Molecular Medicine, Department of Clinical Immunology University of Copenhagen, Denmark
    • ,
  • Lars Vindeløv

      Affiliations

    • The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark
    • The Bone Marrow Transplantation Unit, Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark

Received 21 July 2009; accepted 3 October 2009. published online 12 October 2009.

Several studies have demonstrated that genetic variation in cytokine genes can modulate the immune reactions after allogeneic hematopoietic cell transplantation (HCT). High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen presenting cells (APCs) and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases, and we have recently found the variation in the HMGB1 gene to be associated with mortality in patients with systemic inflammatory response syndrome. To assess the impact of the genetic variation in HMGB1 on outcome after allogeneic HCT, we genotyped 276 and 146 patient/donor pairs treated with allogeneic HCT for hematologic malignancies following myeloablative (MA) or nonmyeloablative (NMA) conditioning. Associations between genotypes and outcome were only observed in the cohort treated with MA conditioning. Patient homozygosity or heterozygosity for the–1377delA minor allele was associated with increased risk of relapse (hazard ratio [HR] 2.11, P = .02) and increased relapse related mortality (RRM) (P = .03). Furthermore, patient homozygosity for the 3814C > G minor allele was associated with increased overall survival (OS; HR 0.13, P = .04), progression free survival (PFS; HR 0.30, P = .05) and decreased probability of RRM (P = .03). Patient carriage of the 2351insT minor allele reduced the risk of grade II to IV acute graft-versus-host disease (aGVHD) (HR 0.60, P = .01), whereas donor homozygosity was associated with chronic GVHD (cGVHD) (HR 1.54, P = .01). Our findings suggest that the inherited variation in HMGB1 is associated with outcome after allogeneic HCT following MA conditioning. None of the polymorphisms were associated with treatment-related mortality (TRM).

Key Words: Genetic polymorphism, High mobility group box 1 protein, HMGB1, Allogeneic hematopoietic cell transplantation

 

 Financial disclosure: See Acknowledgments on page 250.

PII: S1083-8791(09)00458-3

doi:10.1016/j.bbmt.2009.10.002

Biology of Blood and Marrow Transplantation
Volume 16, Issue 2 , Pages 239-252, February 2010

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