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
| Autor: | James R. Downing, Queenie P. Vong, Guolian Kang, Kwan Gan, Ying Li, Yinmei Zhou, Victoria Turner, Wing Keung Chan, Cheng Cheng, Rafijul Bari, Wing Leung, Sheila A. Shurtleff, Christine Hartford, Ching-Hon Pui |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_treatment Down-Regulation Repressor Graft vs Host Disease chemical and pharmacologic phenomena Genome-wide association study Disease Hematopoietic stem cell transplantation Biology Genome Polymorphism Single Nucleotide Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor medicine HLA-DR Humans HLA-DR Antigen 030304 developmental biology 0303 health sciences Multidisciplinary Nucleotides Incidence Homozygote Hematopoietic Stem Cell Transplantation Dendritic Cells HLA-DR Antigens Allografts Molecular biology 3. Good health Repressor Proteins 030220 oncology & carcinogenesis Immunology Acute Disease Female Genome-Wide Association Study |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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