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; Kenneth 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

Transplant Cell Ther. 2021 Oct;27(10):836.e1-836.e7. doi: 10.1016/j.jtct.2021.06.019. Epub 2021 Jun 23.

Authors

Affiliations

¹ Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota. Electronic address: spector@umn.edu.
² Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota.
⁴ University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota.
⁵ Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
⁶ College of Pharmacy, The Ohio State University, Columbus, Ohio.
⁷ Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
⁸ Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
⁹ University of Colorado Denver, Children's Cancer and Blood Disorders, Denver, Colorado.

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.

Keywords: Unrelated donor transplant; acute graft-vs-host disease; mitochondria; outcomes; transplant.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Haplotypes
Hematopoietic Stem Cell Transplantation*
Humans
Leukocytes, Mononuclear
Mitochondria
Pilot Projects
Unrelated Donors*

Abstract

Publication types

MeSH terms

Grants and funding