TY - JOUR
T1 - Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation
AU - Hahn, Theresa
AU - Wang, Junke
AU - Preus, Leah M.
AU - Karaesmen, Ezgi
AU - Rizvi, Abbas
AU - Clay-Gilmour, Alyssa I.
AU - Zhu, Qianqian
AU - Wang, Yiwen
AU - Yan, Li
AU - Liu, Song
AU - Stram, Daniel O.
AU - Pooler, Loreall
AU - Sheng, Xin
AU - Haiman, Christopher A.
AU - Berg, David Van Den
AU - Webb, Amy
AU - Brock, Guy
AU - Spellman, Stephen R.
AU - Onel, Kenan
AU - McCarthy, Philip L.
AU - Pasquini, Marcelo C.
AU - Sucheston-Campbell, Lara E.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - acute leukemia
KW - allogeneic BMT
KW - genome-wide association study
KW - mortality
KW - myelodysplastic syndrome
UR - http://www.scopus.com/inward/record.url?scp=85119213149&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2021.101093
DO - 10.1016/j.eclinm.2021.101093
M3 - Article
AN - SCOPUS:85119213149
SN - 2589-5370
VL - 40
JO - eClinicalMedicine
JF - eClinicalMedicine
M1 - 101093
ER -