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

Blood. 2017 Sep 28;130(13):1585-1596. doi: 10.1182/blood-2017-05-784637. Epub 2017 Aug 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*
  • Validation Studies as Topic*