Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation.
Blood
; 126(25): 2752-63, 2015 Dec 17.
Article
en En
| MEDLINE
| ID: mdl-26432889
ABSTRACT
Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500 568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1589 unrelated bone marrow transplants matched for HLA-A, -B, -C, -DRB1, and -DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association between HLA-DPB1 disparity (P = 4.50 × 10(-9)) and grade II-IV aGVHD development, providing proof of concept for the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, whereby association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified 3 novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10(-11)) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup, sharing HLA-DQB1*0601. Our result suggested that a GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD.
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Bases de datos:
MEDLINE
Asunto principal:
Antígenos de Histocompatibilidad Menor
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Trasplante de Células Madre Hematopoyéticas
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Enfermedad Injerto contra Huésped
Tipo de estudio:
Screening_studies
Límite:
Adolescent
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Adult
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Aged
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Revista:
Blood
Año:
2015
Tipo del documento:
Article