The Distance Between Us: The Landscape of Recipient-Specific Loss-of-Function in Solid Organ Transplantation and Association with Rejection-Free Graft Survival.
1Department of Surgery, The Penn Transplant Institute, Philadelphia, PA
2Center for Clinical Epidemiology and Biostatistics, The Institute for Biomedical Informatics, Philadelphia, PA
3Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
4Department of Surgery, Division of Transplant, the Children's Hospital of Philadelphia, Philadelphia, PA
5The Omics Working Group, iGeneTRAiN Consortium, Philadelphia, PA.
Meeting: 2016 American Transplant Congress
Abstract number: D304
Keywords: Alloantigens, Allorecognition, Donors, Epitopes, unrelated
Session Information
Session Name: Poster Session D: Late Breaking
Session Type: Poster Session
Date: Tuesday, June 14, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
Purpose: This study aims to comprehensively identify genes that are inactivated in both copies in transplant recipients but not in their respective donors, uncovering a landscape of potentially immunogenic non-self proteins.
Methods: We designed a massively parallelized computational pipeline to extract annotated variant calls from genomic data derived from transplant donors and recipients in the iGeneTRAiN consortium. Initiating the pipeline with phased genetic variants, we demonstrate the ability to extract loss-of-function (LoF) annotations at the allele level. Subsequent pairing of transplant recipients with their respective donors allows identification of recipient-specific two-copy LoF genes, providing a set of features which may be recognized as nonself.
Results: A total of 17,325 DNA samples from 30 individual transplant studies were ge+notyped using GWAS arrays as part of the iGeneTRAiN consortium. Phased imputation generated 89,222,664 genetic variants per sample, yielding over 2.9 billion datapoints. Using massively data-parallel high-performance computation, we annotated genetic effects and extracted high-confidence loss-of-function (LoF) mutations. We combined individual phased LoF variants into gene-level annotations, identifying a median of 3,742 autosomal genes containing LoF annotations in either one or two copies (IQR: 3,162-5,164). We then paired transplant donors and recipients for three liver transplant studies, identifying a mean of 36-45 genes that are annotated as LoF in both copies in the recipient but have at least one unannotated gene copy in the respective donor.
Conclusions: We conclude that 1) recipient-specific two-copy loss-of-function (LoF) genes are identifiable via a computational pipeline, 2) LoF is associated with rejection-free graft survival in liver transplant, and therefore 3) LoF is a component of nonself that may be recognized as alloantigens.
CITATION INFORMATION: Cole B, van Setten J, Keating B. The Distance Between Us: The Landscape of Recipient-Specific Loss-of-Function in Solid Organ Transplantation and Association with Rejection-Free Graft Survival. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Cole B, Setten Jvan, Keating B. The Distance Between Us: The Landscape of Recipient-Specific Loss-of-Function in Solid Organ Transplantation and Association with Rejection-Free Graft Survival. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/the-distance-between-us-the-landscape-of-recipient-specific-loss-of-function-in-solid-organ-transplantation-and-association-with-rejection-free-graft-survival/. Accessed May 10, 2025.« Back to 2016 American Transplant Congress