Large-scale genotyping to improve transplantation success

The average lifetime of an organ transplant is about five to ten years before rejection ensues. Patients often require multiple replacement surgeries and are on immunosuppressants for the rest of their lives, which can result in drug-induced liver toxicity. In the US alone, there are currently more than 110,000 people awaiting transplant. Each year, about 7,000 will die while on the waiting list. Dr. Brendan Keating and his colleagues in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) have collaborated with the UK Biobank and Affymetrix to develop an array that enables large-scale genotyping to better understand the genomic factors that contribute to transplant rejection.

The current standard practice for pairing organ donors with recipients is to match human leukocyte antigen (HLA) genes or blood type. Even with an HLA match, rejection still occurs in a high percentage of transplant patients. The aim of this new work is to find additional transplant-related genes, as well as genes that affect the metabolism of immunosuppressant drugs. To build the customized genotyping array for this study, the team compiled CNVs, SNVs, and SNPs from UK Biobank Axiom® Array and Axiom® Biobank Genotyping Array. The array is comprised of more than 780,000 genome-wide variants tailored for deeper capture of variants across HLA, killer-cell immunoglobulin-like receptors, pharmacogenomic genes, and metabolic loci that are important in transplantation. This array development is the first investigation to date that includes non-HLA genetic determinants of clinical outcomes following organ transplantation.

"We've never before had the tools or
the sample numbers to investigate these non-HLA genetic associations."

iGeneTRAiN aims to improve clinical transplantation success through the discovery of immunological markers and through a deeper understanding of the genomic factors that contribute to graft rejection, other transplant complications, and the metabolism of immunosuppressant drugs. The consortium has already generated genomic and outcomes data for more than 32,000 organ donors and recipients. Findings from these studies will provide insights into genomic incompatibility of donor-recipient (D-R) pairs, facilitate improved D-R matching, and identify therapeutic targets that can be used in the development of personalized immunosuppressive therapies.

Genomic underpinnings of rejection and complications in transplantation