Dataset Information

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

ABSTRACT:

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 × 10−8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24–1.56, p = 3.3 × 10−8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21–1.48, p = 2.0 × 10−8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41–2.05, p = 3.15 × 10−8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49–2.31, p = 2.84 × 10−8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31–1.73, p = 6.9 × 10−9) and CT49 (rs32250, HR = 1.44, 95% CI1.26–1.64, p = 2.6 × 10−8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74–3.12, p = 1.26 × 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 × 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.

Funding

This project was funded by grants from the National Institutes of Health, USA

SUBMITTER: Hahn T

PROVIDER: S-EPMC8548922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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