TNFSF4 is a costimulatory molecule that is important for T cell activation. In this study, we used multivariate Cox regression models to determine whether a single nucleotide polymorphism (SNP) in TNFSF4 is associated with outcomes in 1370 HLA-A, B, C, DRB1 and DQB1 high resolution matched unrelated donor hematopoietic stem cell transplantations (HCT). HCT were performed between 1990 and 2002, with 92% of patients receiving grafts from bone marrow compared to 8% peripheral blood. The median age at transplant was 37 years. Disease diagnoses included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Disease staging was stratified into early (45%) intermediate (31%) and advanced (24%) at the time of transplant. A majority of graft versus host disease prophylaxis consisted of cyclosporine (60%) or tacrolimus (20%) with methotrexate, while 16% of the patients received T-cell depletion. Our analysis found that patients with donors homozygous for the C variant of SNP rs10912564 (48%) had better disease-free survival (P= 0.029) and overall survival (P=0.009) with less treatment related mortality (P=0.006). Analysis of the primary cause of death found a lower incidence of death due to infection (P=0.014) in patients with donors carrying the CC genotype. Our in vitro data demonstrate that the C variant has a much higher affinity for the nuclear transcription factor, Myb providing a possible mechanism for how the variant might be functional. These results suggest that HLA matched HCT using an unrelated donor with the rs10912564 CC genotype in TNFSF4 is associated with increased patient survival.

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