Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation

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 (p < 5 x 10(-8)) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 x 10(-8)) and donor-recipient genotype mismatch with OS at LINCO2774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 x 10(-8)); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 x 10(-8)), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 x 10(-8)), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 x 10(-9)) and CT49 (rs32250, HR = 1.44, 95% Cl1.26-1.64, p = 2.6 x 10(-8)); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 x 10(-8)) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 x 10(-9)). 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. (C) 2021 The Author(s). Published by Elsevier Ltd.