Non-APOL1 genetic factors and kidney transplant outcomes

Abstract This is an ancillary study to the prospective APOLLO (APOL1 Long-term Kidney Transplantation Outcomes) cohort of 2,800 kidney transplant donor-recipient pairs. The parent study aims to test the impact of APOL1 risk genotypes on kidney transplantation outcomes. Here, we propose to test the role of additional genetic factors other than APOL1 in determining allograft outcomes. Accordingly, we propose to expand the scope of the APOLLO study to generate high-quality genome-wide SNP and exome sequence data for all 2,800 donor- recipient pairs enrolled by the network. Our proposal addresses the existing disparities in research and clinical care, since African-ancestry patients with end stage kidney disease are currently under-represented in genetic studies and have worse transplantation outcomes compared to non-African ancestry patients. Our overarching hypothesis is that there are multiple additional genetic factors in this population that convey the risk of allograft loss independently of APOL1. Our recent work clearly demonstrates that polygenic background and APOL1 risk genotypes have additive effects on the risk of kidney disease in individuals of African ancestry. Our newly proposed genome-wide polygenic score (GPS) combining polygenic and APOL1 risk provided substantially improved prediction of kidney disease. There is now an urgent need to test whether combining donor polygenic and APOL1 risk improves the prediction of allograft outcomes. Additionally, our proposed generation of genome-wide genetic data will facilitate unbiased scans for specific APOL1 modifiers with an effect on graft survival. Lastly, the APOLLO study provides us with a unique opportunity to perform genetic compatibility scans in full donor-recipient pairs. We aim to test our original “genomic collision” hypothesis at the LIMS1 locus under which the recipients carrying gene-disrupting variants are at a higher risk of rejection when exposed to a graft expressing intact gene products. We will then expand this hypothesis to various types of genetic variation genome-wide, including gene-disrupting copy number variants, predicted loss-of-function variants, and even missense variants. Any positive findings from our discovery studies will be tested for validation in the ancestrally diverse international cohorts of the iGeneTRAiN consortium. Our experienced team of investigators from the fields of human genetics, precision medicine, kidney transplant epidemiology, and statistics has a track record of successful collaboration and execution of genetic studies involving thousands of participants. We believe this proposal will challenge the existing clinical paradigms in kidney transplantation, and our expert team is ideally positioned to lead this effort.