Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR

Logan G. Spector; Stephen R Spellman; Bharat Thyagarajan; Kenny B Beckman; Cody Hoffmann; John Garbe; Theresa Hahn; Lara Sucheston-Campbell; Michaela Richardson; Todd E De For; Jakub Tolar; Michael R Verneris

doi:10.1016/j.jtct.2021.06.019

Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR

Logan G. Spector, Stephen R Spellman, Bharat Thyagarajan, Kenny B Beckman, Cody Hoffmann, John Garbe, Theresa Hahn, Lara Sucheston-Campbell, Michaela Richardson, Todd E De For, Jakub Tolar, Michael R Verneris

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

Abstract

Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and.39, respectively) or grade III-IV aGVHD (P =.68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.

Original language	English (US)
Pages (from-to)	836.e1-836.e7
Journal	Transplantation and Cellular Therapy
Volume	27
Issue number	10
DOIs	https://doi.org/10.1016/j.jtct.2021.06.019
State	Published - Oct 2021

Bibliographical note

Funding Information:
We acknowledge the contribution of the late Dr. Julie Ross, who was a leader of the pilot and co-Principal Investigator of the grant (R01CA196754), which supported the current study. Financial disclosure: none. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: Logan G. Spector and Michael R. Verneris conceived the study, obtained funding, oversaw assay and analysis, and jointly drafted the manuscript. Stephen R. Spellman assisted with sample and data acquisition. Bharat Thyagarajan and Jakub Tolar assisted with study conception, obtaining funding, assay, analysis, and critical editing of the manuscript. Theresa Hahn and Lara Sucheston-Campbell contributed principle components data from genomewide arrays of overlapping subjects and provided critical editing of the manuscript. Kenneth B. Beckman, Cody Hoffmann, and John Garbe developed the mitochondrial sequencing assay and processed the completed sequence data, as well as critically edited the manuscript. Michaela Richardson and Todd E. De For conducted statistical analysis and provided critical editing of the manuscript.

Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy

Keywords

Unrelated donor transplant
acute graft-vs-host disease
mitochondria
outcomes
transplant

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Spector, L. G., Spellman, S. R., Thyagarajan, B., Beckman, K. B., Hoffmann, C., Garbe, J., Hahn, T., Sucheston-Campbell, L., Richardson, M., De For, T. E., Tolar, J., & Verneris, M. R. (2021). Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR. Transplantation and Cellular Therapy, 27(10), 836.e1-836.e7. https://doi.org/10.1016/j.jtct.2021.06.019

Spector, LG, Spellman, SR, Thyagarajan, B , Beckman, KB, Hoffmann, C, Garbe, J, Hahn, T, Sucheston-Campbell, L, Richardson, M, De For, TE , Tolar, J & Verneris, MR 2021, 'Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR', Transplantation and Cellular Therapy, vol. 27, no. 10, pp. 836.e1-836.e7. https://doi.org/10.1016/j.jtct.2021.06.019

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abstract = "Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and.39, respectively) or grade III-IV aGVHD (P =.68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.",

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author = "Spector, {Logan G.} and Spellman, {Stephen R} and Bharat Thyagarajan and Beckman, {Kenny B} and Cody Hoffmann and John Garbe and Theresa Hahn and Lara Sucheston-Campbell and Michaela Richardson and {De For}, {Todd E} and Jakub Tolar and Verneris, {Michael R}",

note = "Funding Information: We acknowledge the contribution of the late Dr. Julie Ross, who was a leader of the pilot and co-Principal Investigator of the grant (R01CA196754), which supported the current study. Financial disclosure: none. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: Logan G. Spector and Michael R. Verneris conceived the study, obtained funding, oversaw assay and analysis, and jointly drafted the manuscript. Stephen R. Spellman assisted with sample and data acquisition. Bharat Thyagarajan and Jakub Tolar assisted with study conception, obtaining funding, assay, analysis, and critical editing of the manuscript. Theresa Hahn and Lara Sucheston-Campbell contributed principle components data from genomewide arrays of overlapping subjects and provided critical editing of the manuscript. Kenneth B. Beckman, Cody Hoffmann, and John Garbe developed the mitochondrial sequencing assay and processed the completed sequence data, as well as critically edited the manuscript. Michaela Richardson and Todd E. De For conducted statistical analysis and provided critical editing of the manuscript. Publisher Copyright: {\textcopyright} 2021 The American Society for Transplantation and Cellular Therapy",

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N1 - Funding Information: We acknowledge the contribution of the late Dr. Julie Ross, who was a leader of the pilot and co-Principal Investigator of the grant (R01CA196754), which supported the current study. Financial disclosure: none. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: Logan G. Spector and Michael R. Verneris conceived the study, obtained funding, oversaw assay and analysis, and jointly drafted the manuscript. Stephen R. Spellman assisted with sample and data acquisition. Bharat Thyagarajan and Jakub Tolar assisted with study conception, obtaining funding, assay, analysis, and critical editing of the manuscript. Theresa Hahn and Lara Sucheston-Campbell contributed principle components data from genomewide arrays of overlapping subjects and provided critical editing of the manuscript. Kenneth B. Beckman, Cody Hoffmann, and John Garbe developed the mitochondrial sequencing assay and processed the completed sequence data, as well as critically edited the manuscript. Michaela Richardson and Todd E. De For conducted statistical analysis and provided critical editing of the manuscript. Publisher Copyright: © 2021 The American Society for Transplantation and Cellular Therapy

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Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR

Abstract

Bibliographical note

Keywords

UN SDGs

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