Analysis of a Genetic Polymorphism in the Costimulatory Molecule TNFSF4 with Hematopoietic Stem Cell Transplant Outcomes.
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.
Transplant Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts.
Peter T
PT
Jindra
Transplant Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts.
Susan E
SE
Conway
Genomics Unit, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
Stacy M
SM
Ricklefs
Genomics Unit, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
Stephen F
SF
Porcella
Genomics Unit, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
Sarah L
SL
Anzick
Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
Mike
M
Haagenson
Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Tao
T
Wang
Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
Stephen
S
Spellman
Transplant Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts.
Edgar
E
Milford
Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
Peter
P
Kraft
Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
David H
DH
McDermott
Transplant Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Boston, Massachusetts. Electronic address: rabdi@rics.bwh.harvard.edu.
Reza
R
Abdi
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D001402:B-Lymphocytes; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006680:HLA Antigens / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D053278:OX40 Ligand / Q000235:genetics*; D020626:Oncogene Proteins v-myb / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015996:Survival Rate
D015703:Antigens, CD; D006680:HLA Antigens; D053278:OX40 Ligand; D020626:Oncogene Proteins v-myb; C089251:TNFSF4 protein, human
Costimulation; GVHD; Gene polymorphism; Hematopoietic stem cell transplantation; Infection; Outcomes