title: Genome-wide single-nucleotide polymorphism analysis revealed SUFU suppression of acute graft-versus-host disease through downregulation of HLA-DR expression in recipient dendritic cells.
abstract: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). To identify recipient risk factors, a genome-wide study was performed including 481,820 single-nucleotide polymorphisms (SNPs). Two GVHD susceptibility loci (rs17114803 and rs17114808) within the SUFU gene were identified in the discovery cohort (p = 2.85 × 10(-5)). The incidence of acute GVHD among patients homozygous for CC at SUFU rs17114808 was 69%, which was significantly higher than the 8% rate observed in CT heterozygous patients (p = 0.0002). In an independent validation cohort of 100 patients, 50% of the patients with the CC genotype developed GVHD compared to 8% of the patients with either CT or TT genotype (p = 0.01). In comparison to CC dendritic cells, those from CT expressed higher levels of SUFU mRNA and protein, had lower levels of surface HLA-DR, and induced less allogeneic mixed leukocyte response (MLR). Ectopic expression of SUFU in THP-1 derived DCs reduced HLA-DR expression and suppressed MLR, whereas silencing of SUFU enhanced HLA-DR expression and increased MLR. Thus our findings provide novel evidence that recipient SUFU germline polymorphism is associated with acute GVHD and is a novel molecular target for GVHD prevention and treatment.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Rafijul
authors.initials: R
authors.lastname: Bari
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartford
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Wing Keung
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Queenie
authors.initials: Q
authors.lastname: Vong
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Kwan
authors.initials: K
authors.lastname: Gan
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Yinmei
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Victoria
authors.initials: V
authors.lastname: Turner
authors.affiliation: 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN [3] Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: 1] Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN [2] Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000208:Acute Disease; D064591:Allografts; D045744:Cell Line, Tumor; D005260:Female; D055106:Genome-Wide Association Study; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006720:Homozygote; D006801:Humans; D015994:Incidence; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D012097:Repressor Proteins; C490764:SUFU protein, human