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

Theresa Hahn; Junke Wang; Leah M. Preus; Ezgi Karaesmen; Abbas Rizvi; Alyssa I. Clay-Gilmour; Qianqian Zhu; Yiwen Wang; Li Yan; Song Liu; Daniel O. Stram; Loreall Pooler; Xin Sheng; Christopher A. Haiman; David Van Den Berg; Amy Webb; Guy Brock; Stephen R. Spellman; Kenan Onel; Philip L. McCarthy; Marcelo C. Pasquini; Lara E. Sucheston-Campbell

doi:10.1016/j.eclinm.2021.101093

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

Theresa Hahn
, Junke Wang
, Leah M. Preus
, Ezgi Karaesmen
, Abbas Rizvi
, Alyssa I. Clay-Gilmour
, Qianqian Zhu
, Yiwen Wang
, Li Yan
, Song Liu
, Daniel O. Stram
, Loreall Pooler
, Xin Sheng
, Christopher A. Haiman
, David Van Den Berg
, Amy Webb
, Guy Brock
, Stephen R. Spellman
, Kenan Onel
, Philip L. McCarthy

Marcelo C. Pasquini, Lara E. Sucheston-Campbell

Department of Biostatistics

University at Buffalo

Roswell Park Cancer Institute
Ohio State University
SUNY Buffalo
University of South Carolina
University of Southern California
Center for International Blood and Marrow Transplant Research
Icahn School of Medicine at Mount Sinai
Medical College of Wisconsin

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English
Article number	101093
Journal	eClinicalMedicine
Volume	40
DOIs	https://doi.org/10.1016/j.eclinm.2021.101093
State	Published - Oct 2021

Keywords

acute leukemia
allogeneic BMT
genome-wide association study
mortality
myelodysplastic syndrome

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10.1016/j.eclinm.2021.101093

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Hahn, T., Wang, J., Preus, L. M., Karaesmen, E., Rizvi, A., Clay-Gilmour, A. I., Zhu, Q., Wang, Y., Yan, L., Liu, S., Stram, D. O., Pooler, L., Sheng, X., Haiman, C. A., Berg, D. V. D., Webb, A., Brock, G., Spellman, S. R., Onel, K., ... Sucheston-Campbell, L. E. (2021). Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation. eClinicalMedicine, 40, Article 101093. https://doi.org/10.1016/j.eclinm.2021.101093

@article{fb1197ca61e94c9a852a2e95ecc44b9f,

title = "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.",

keywords = "acute leukemia, allogeneic BMT, genome-wide association study, mortality, myelodysplastic syndrome",

author = "Theresa Hahn and Junke Wang and Preus, \{Leah M.\} and Ezgi Karaesmen and Abbas Rizvi and Clay-Gilmour, \{Alyssa I.\} and Qianqian Zhu and Yiwen Wang and Li Yan and Song Liu and Stram, \{Daniel O.\} and Loreall Pooler and Xin Sheng and Haiman, \{Christopher A.\} and Berg, \{David Van Den\} and Amy Webb and Guy Brock and Spellman, \{Stephen R.\} and Kenan Onel and McCarthy, \{Philip L.\} and Pasquini, \{Marcelo C.\} and Sucheston-Campbell, \{Lara E.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = oct,

doi = "10.1016/j.eclinm.2021.101093",

language = "English",

volume = "40",

journal = "eClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier Ltd.",

}

Hahn, T, Wang, J, Preus, LM, Karaesmen, E, Rizvi, A, Clay-Gilmour, AI, Zhu, Q, Wang, Y, Yan, L, Liu, S, Stram, DO, Pooler, L, Sheng, X, Haiman, CA, Berg, DVD, Webb, A, Brock, G, Spellman, SR, Onel, K, McCarthy, PL, Pasquini, MC & Sucheston-Campbell, LE 2021, 'Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation', eClinicalMedicine, vol. 40, 101093. https://doi.org/10.1016/j.eclinm.2021.101093

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.

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 - https://www.scopus.com/pages/publications/85119213149

U2 - 10.1016/j.eclinm.2021.101093

DO - 10.1016/j.eclinm.2021.101093

M3 - Article

SN - 2589-5370

VL - 40

JO - eClinicalMedicine

JF - eClinicalMedicine

M1 - 101093

ER -

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

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Keywords

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