title: Single nucleotide polymorphisms in the NOD2/CARD15 gene are associated with an increased risk of relapse and death for patients with acute leukemia after hematopoietic stem-cell transplantation with unrelated donors.
abstract: OBJECTIVE
  Hematopoietic stem cell transplantation (HSCT) is an important option in the management of acute leukemia, but the risk of disease relapse and death remains appreciable. Recent studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15) gene single nucleotide polymorphisms (SNPs), implicated in innate immunity and Crohn's disease, may also affect immune function post-HSCT.
  
  
  METHODS
  NOD2/CARD15 genotypes were analyzed in 196 patients diagnosed with acute leukemia and their unrelated donors. The pairs are part of a previously well-characterized cohort with a median follow-up of 2.2 years (range, 0.42 to 6.61 years). T-cell depletion was used in 83% of pairs.
  
  
  RESULTS
  NOD2/CARD15 SNPs were associated with a reduction in overall survival (44% v 22%; log-rank P = .0087) due to an increase in disease relapse (32% v 54%; Gray's test P = .001) as compared with wild-type pairs. In multivariate analyses, the two most significant factors impacting outcome were transplantation in relapse and the presence of SNPs. The incidence of acute graft-versus-host disease was low and there was no significant difference due to the presence of SNPs.
  
  
  CONCLUSIONS
  These data indicate an unrecognized role for the NOD2/CARD15 gene in unrelated donor HSCT for acute leukemia. The increased risk of disease relapse suggests that the wild-type gene product may contribute to a graft-versus-leukemia effect. These data suggest that NOD2/CARD15 genotyping before transplantation may contribute to prognosis and influence clinical management.
authors.affiliation: Anthony Nolan Research Institute, Royal Free Hospital, London, United Kingdom.
authors.forename: Neema P
authors.initials: NP
authors.lastname: Mayor
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Shaw
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Hazael
authors.initials: H
authors.lastname: Maldonado-Torres
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.forename: Satish
authors.initials: S
authors.lastname: Keshav
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality* / Q000628:therapy*; D012008:Recurrence
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein