Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant

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...

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Bibliographic Details
Published in:Blood 2017-09, Vol.130 (13), p.1585-1596
Main Authors: Karaesmen, Ezgi, Rizvi, Abbas A., Preus, Leah M., McCarthy, Philip L., Pasquini, Marcelo C., Onel, Kenan, Zhu, Xiaochun, Spellman, Stephen, Haiman, Christopher A., Stram, Daniel O., Pooler, Loreall, Sheng, Xin, Zhu, Qianqian, Yan, Li, Liu, Qian, Hu, Qiang, Webb, Amy, Brock, Guy, Clay-Gilmour, Alyssa I., Battaglia, Sebastiano, Tritchler, David, Liu, Song, Hahn, Theresa, Sucheston-Campbell, Lara E.
Format: Article
Language:English
Subjects:
Allografts
Bone Marrow Transplantation - mortality
Disease-Free Survival
Genome-Wide Association Study
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - mortality
Leukemia, Myeloid, Acute - therapy
Myelodysplastic Syndromes - genetics
Myelodysplastic Syndromes - mortality
Myelodysplastic Syndromes - therapy
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality
Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy
Stem Cell Transplantation - mortality
Transplantation
Validation Studies as Topic
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Summary: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. •Candidate SNP associations with survival outcomes after URD transplant are most likely false-positive findings.•Over 85% of candidate SNPs are not linked to a biochemical function; of those that are, about half are not linked to the candidate gene.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2017-05-784637