title: Association of HMGB1 polymorphisms with outcome after allogeneic hematopoietic cell transplantation.
abstract: 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).
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, University of Copenhagen, Denmark. brian.kornblit@rh.regionh.dk
authors.forename: Brian
authors.initials: B
authors.lastname: Kornblit
authors.forename: Tania
authors.initials: T
authors.lastname: Masmas
authors.forename: Søren L
authors.initials: SL
authors.lastname: Petersen
authors.forename: Hans O
authors.initials: HO
authors.lastname: Madsen
authors.forename: Carsten
authors.initials: C
authors.lastname: Heilmann
authors.forename: Lone
authors.initials: L
authors.lastname: Schejbel
authors.forename: Henrik
authors.initials: H
authors.lastname: Sengeløv
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
authors.forename: Lars
authors.initials: L
authors.lastname: Vindeløv
mesh_terms: D019046:Bone Marrow Neoplasms / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006086:Graft vs Host Disease / Q000235:genetics; D024243:HMGB1 Protein / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D019653:Myeloablative Agonists / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D013223:Statistics as Topic; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D024243:HMGB1 Protein; D019653:Myeloablative Agonists