Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant.
Blood
; 130(13): 1585-1596, 2017 09 28.
Article
en En
| MEDLINE
| ID: mdl-28811306
ABSTRACT
Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Trasplante de Médula Ósea
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Supervivencia sin Enfermedad
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Polimorfismo de Nucleótido Simple
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Trasplante de Células Madre
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Estudios de Validación como Asunto
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Estudio de Asociación del Genoma Completo
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article