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Genetic Associations in Acute Leukemia Patients after Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Rizvi, Abbas Ali
http://rave.ohiolink.edu/etdc/view?acc_num=osu1555285409458706

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Pharmacy.
HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) is used as a potential curative therapy for otherwise fatal hematological cancers, including but not limited to acute and chronic leukemia, Hodgkin and non-Hodgkin lymphoma, and myelodysplastic syndrome (MDS). MUD-HSCT involves the transfer of healthy individual (donor) bone marrow stem cells to an unhealthy patient (recipient). Despite improvements in human leukocyte antigen (HLA) matching algorithms, treatment protocols and patient care overall survival (OS) rates profoundly decrease in the first 1-year post-transplant. The largest predictor of mortality during this time frame is HLA matching, emphasizing the importance of genetic variation in determining survival. Despite the clear importance of genetics to survival following transplant, the relationship of non-HLA genetic variation remains underexplored. In this dissertation, we characterized and explored the independent and joint non-HLA genetic contributions to survival outcomes in donors and recipients with acute leukemias or MDS using pre-existing genome-wide association study (GWAS), Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT), a study of 3,532 donor-recipient pairs with survival, clinical and genomic data available. We used DISCOVeRY-BMT to replicate or validate all previous literature that investigated survival outcomes after allogeneic HSCT. None of the previous literature was reproduced, likely due to the previous cohorts comprising heterogeneous samples (testing with multiple diseases) or small sample sizes. Next we developed an R/Bioconductor software package called gwasurvivr. This package takes input from popular genomics software and performs multivariate Cox regression survival analysis in a scalable and efficient manner. We integrated gwasurvivr into an automated pipeline that performs full survival GWAS analyses and conducts meta-analysis. We conducted this on numerous subsets of DISCOVeRY-BMT. Here, we report only post-HSCT genetic associations for acute lymphoblastic leukemia (ALL) subset of DISCOVeRY-BMT GWAS. We found SNPs associated to recipients for the outcomes overall survival (OS), disease related mortality (DRM), and organ failure (OF). We also found donor SNPs associated with OS, transplant-related mortality (TRM), DRM, and graft-versus host disease (GVHD). Lastly, we probed our findings for biological relevance (affecting gene expression or transcription factor binding) by annotating associated SNPs using publicly available databases.
Lara Sucheston-Campbell, PhD (Advisor)
Guy Brock, PhD (Committee Member)
Moray Campbell, PhD (Committee Member)
Shili Lin, PhD (Committee Member)
126 p.
Bioinformatics; Biostatistics; Epidemiology; Genetics; Pharmaceuticals; Statistics
Leukemia, Survival Analysis, Genomics, Hematopoietic Stem Cell Transplantation, Genetic Associations, GWAS, R Bioconductor, Bone Marrow Transplant, gwasurvivr, Genomics

Recommended Citations

Citations

  • Rizvi, A. A. (2019). Genetic Associations in Acute Leukemia Patients after Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555285409458706

    APA Style (7th edition)

  • Rizvi, Abbas. Genetic Associations in Acute Leukemia Patients after Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1555285409458706.

    MLA Style (8th edition)

  • Rizvi, Abbas. "Genetic Associations in Acute Leukemia Patients after Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555285409458706

    Chicago Manual of Style (17th edition)

osu1555285409458706
423
© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.