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

EClinicalMedicine. 2021 Aug 25:40:101093. doi: 10.1016/j.eclinm.2021.101093. eCollection 2021 Oct.

Authors

Theresa Hahn¹, Junke Wang², Leah M Preus³, Ezgi Karaesmen², Abbas Rizvi², Alyssa I Clay-Gilmour⁴, Qianqian Zhu⁵, Yiwen Wang², Li Yan⁵, Song Liu⁵, Daniel O Stram⁶, Loreall Pooler⁶, Xin Sheng⁶, Christopher A Haiman⁶, David Van Den Berg⁶, Amy Webb⁷, Guy Brock⁷, Stephen R Spellman⁸, Kenan Onel⁹, Philip L McCarthy¹, Marcelo C Pasquini¹⁰, Lara E Sucheston-Campbell^{2

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Affiliations

¹ Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
² College of Pharmacy, The Ohio State University, Columbus, OH, USA.
³ Department of Epidemiology and Environmental Health, State University of New York at Buffalo, Buffalo, NY, USA.
⁴ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
⁵ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁶ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
⁸ Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA.
⁹ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA.
¹¹ College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.

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.

Keywords: acute leukemia; allogeneic BMT; genome-wide association study; mortality; myelodysplastic syndrome.

Abstract

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