Adaptive sequencing in transplantation: identifying immune-genomic risk profiles | LC 25

Biography

Dr Karen Sherwood graduated from the University of Edinburgh and completed post-doctoral training in genetics, computational biology and immunology at the Roslin Institute in Scotland and the Heart Lung Institute in Vancouver. She is Director of the British Columbian Provincial Transplant Immunology Department at Vancouver General Hospital, Co-Principal Investigator and scientific Lead for the Genome Canada Transplant Consortium program, and Cluster Director for University of British Columbia Precision Transplant Cluster.

Abstract

Transplantation is a life-saving therapy but carries significant risks, including rejection, graft-versus-host disease, infection, and malignancy, which can lead to failure and death. These complications arise from the interaction between the recipient's immune system and the transplanted organ, requiring long-term toxic drugs to prevent immune injury. Traditional pre-transplant assessment focuses on 11 human leukocyte antigen (HLA) genes, but advancing technologies now allow for the assessment of many more genes relevant to graft tolerance. We are using adaptive sequencing to pre-emptively identify patients at risk for lethal complications and to personalize treatment strategies. We have established flexible adaptive sequencing pipelines that include traditional HLA genes, ABO, other blood group histocompatibility genes, pharmacogenomics loci, or whole chromosomal arms (e.g. 6p or Xp for loss of heterozygosity determination). By testing different browser extensible data files, run parameters, and flow cells (GridION, PromethION) we currently achieve up to 5.5x enrichment, which is sufficient for variant calling and loss of heterozygosity analyses. Our goal is to develop individual immune-genomic risk profiles for transplant patients and identify key polygenic predictors of treatment response to minimize toxic immunosuppression. We have achieved dramatic success in reducing early immune injury through the combination of molecular diagnostics and structural biology. This research represents the next critical step to refine precision medicine, improve long-term patient outcomes, reduce healthcare costs, and enhance the quality and duration of life for transplant recipients in Canada and globally. Incorporating comprehensive genomic information into clinical decision-making will be crucial for reducing and eventually eliminating toxic immunosuppressive drugs through operational tolerance.