HLA donor-recipient (D-R) matching is critical for graft outcomes following Kidney, Heart, Lung and hematopoietic cell transplantation. Genetic association studies in large well-characterized transplant cohorts are lacking and there is a clear need to characterize how MHC and KIR genetic variants underpin transplantation outcomes. The International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) was formed to increase the understanding of the genetic architecture of transplant outcomes, by bringing together transplantation studies with genome-wide association study (GWAS) datasets from >52,600 recipients/donors across well-curated heart, kidney, liver and lung transplant phenotype datasets. This constitutes the largest solid-organ transplant consortium ever assembled. A strategic Pharma collaboration where we sequence key HLA Class I and II in the majority of iGeneTRAiN studies, and additional MHC/KIR regions in subsets of studies, is facilitating ample statistical power to assess association studies of HLA and KIR with key transplant-related outcomes. A large portion of the iGeneTRAiN database is derived from non-European ancestry samples, which greatly addresses the lack of adequate MHC/KIR genetic data in these populations.
Our overarching aim of this application is to accelerate the discovery of MHC and KIR genetic variants underpinning transplant-related phenotypes/outcomes. To achieve this aim, we will use complementary genomic approaches (short-read and amplicon-based HLA Class I/II second generation sequencing, and long-read sequencing approaches). We will also employ a number of innovative analyses pipelines to maximize the associative potential of very large genetic (genotyping and sequencing) and phenotypic datasets that are derived from well-curated solid organ samples.
