Analysis of a Genetic Polymorphism in the Costimulatory Molecule TNFSF4 with Hematopoietic Stem Cell Transplant Outcomes

Biol Blood Marrow Transplant. 2016 Jan;22(1):27-36. doi: 10.1016/j.bbmt.2015.08.037. Epub 2015 Sep 5.


Despite stringent procedures to secure the best HLA matching between donors and recipients, life-threatening complications continue to occur after hematopoietic stem cell transplantation (HSCT). Studying single nucleotide polymorphism (SNP) in genes encoding costimulatory molecules could help identify patients at risk for post-HSCT complications. In a stepwise approach we selected SNPs in key costimulatory molecules including CD274, CD40, CD154, CD28, and TNFSF4 and systematically analyzed their association with post-HSCT outcomes. Our discovery cohort analysis of 1157 HLA-A, -B, -C, -DRB1, and -DQB1 matched cases found that patients with donors homozygous for the C variant of rs10912564 in TNFSF4 (48%) had better disease-free survival (P = .029) and overall survival (P = .009) with less treatment-related mortality (P = .006). Our data demonstrate the TNFSF4C variant had a higher affinity for the nuclear transcription factor Myb and increased percentage of TNFSF4-positive B cells after stimulation compared with CT or TT genotypes. However, these associations were not validated in a more recent cohort, potentially because of changes in standard of practice or absence of a true association. Given the discovery cohort, functional data, and importance of TNFSF4 in infection clearance, TNFSF4C may associate with outcomes and warrants future studies.

Keywords: Costimulation; GVHD; Gene polymorphism; Hematopoietic stem cell transplantation; Infection; Outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, CD
  • B-Lymphocytes
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Disease-Free Survival
  • Female
  • HLA Antigens / genetics
  • Hematologic Neoplasms / genetics*
  • Hematologic Neoplasms / mortality
  • Hematologic Neoplasms / pathology
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Homozygote*
  • Humans
  • Infant
  • Male
  • Middle Aged
  • OX40 Ligand / genetics*
  • Oncogene Proteins v-myb / genetics
  • Polymorphism, Single Nucleotide
  • Survival Rate


  • Antigens, CD
  • HLA Antigens
  • OX40 Ligand
  • Oncogene Proteins v-myb
  • TNFSF4 protein, human