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Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation. | LitMetric
Background : Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.Methods : We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.Findings : Using meta-analyses of both cohorts, genome-wide significant associations ( < 5 × 10) were identified in: recipient genomes with OS at (rs9990017, HR = 1.4, 95% CI 1.24-1.56, = 3.3 × 10) and donor-recipient genotype mismatch with OS at (rs10927108, HR = 1.34, 95% CI 1.21-1.48, = 2.0 × 10); donor genomes with DRM at (rs79076914, HR = 1.7, 95% CI 1.41-2.05, = 3.15 × 10), (rs79498125, HR = 1.86, 95% CI 1.49-2.31, = 2.84 × 10), (rs2167710, HR = 1.5, 95% CI 1.31-1.73, = 6.9 × 10) and (rs32250, HR = 1.44, 95% CI1.26-1.64, = 2.6 × 10); recipient genomes at with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, = 1.26 × 10) and donor-recipient genotype mismatch between and with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, = 4.6 × 10). Results publicly available at https://fuma.ctglab.nl/browse.Interpretation : These data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.Funding : This project was funded by grants from the National Institutes of Health, USA.
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