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Extended histocompatibility : genomic prediction of kidney transplant outcome

Year: 2024
Type: dissertation
Study design: Observational Study
Abstract: Kidney transplantation is an established, cost-effective treatment for patients with an endstage kidney disease. The annual number of kidney transplantations performed in Finland is approximately 250. A hurdle in all transplantations between two individuals is the immunological recognition of the transplanted graft as foreign by the recipient. This often leads to immunological attack against the graft. The goal of the prior histocompatibility testing between the recipient and organ donor is to find the immunologically most suitable transplant for each patient and this way to reduce complications and immunization against the graft. Despite current histocompatibility testing, we are unable to adequately predict severe transplantation-related complications, such as rejection. Genomic screenings of risk factors outside the HLA genes for organ transplantation complications and long-term survival started in the last decade. Genome-wide association studies (GWAS) have reported variants that are associated with kidney transplant outcomes. In addition to effects of single variants, the genomic risk can also be estimated by combining all low-level effects of GWAS results into polygenic risk scores (PRS). An approach particular to transplantation is to study genome-level matching between donor and patient. Transplantation involves an interaction of two independent genomes, and resulting mismatches have complex mechanisms and potentially larger effect sizes than conferred by donor or recipient variants alone. The aim of the thesis was to identify novel non-HLA genomic risk factors that could be utilized to predict more accurately the outcome of kidney transplantation. The genome variation between kidney transplantation recipient and brain-dead donor was determined in a retrospective adult kidney transplantation cohort. The Finnish cohort included 1,025 kidney transplantation patient-donor pairs transplanted at the Helsinki University Hospital between 2007 and 2017. The association of the genome-wide compatibility with the transplantation outcomes were estimated using statistical methods. This thesis also utilized PRS estimates for the major causes of death of the graft donor in predicting the outcomes of kidney transplantation. In the future, with the help of genomic information, we may be able to create better tools to predict transplant complications and long-term survival, and to understand the mechanisms behind extended histocompatibility.
Language: English
Subfield: Transplantation
Field: Medicine
Open Access status: green
OpenAlex ID: W7202012148
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