Govender, Melanie Ann2025-10-302024Govender, Melanie Ann. (2024). Determining the risk profile for chronic kidney disease (CKD) in rural South Africans using genetic risk scores and protein markers [PhD thesis, University of the Witwatersrand, Johannesburg]. WIReDSpace.https://hdl.handle.net/10539/47282A research report submitted in fulfillment of the requirements for the Doctor of Philosophy, in the Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, 2024Chronic kidney disease (CKD) is a global public health concern, with disproportionate morbidity and mortality in low- and middle-income regions, including Sub-Saharan Africa. Recent advancements in multi-omics approaches have explored disease risk indicators and contributed to the understanding of the pathophysiology of CKD in high-income populations. The overall aim of this research was to assess and understand CKD in a Sub- Saharan population using genetic risk models for kidney disease and to evaluate the proteomic profile of individuals with hypertension-associated albuminuria, with a view to detecting indicators of CKD and disease progression in a Sub-Saharan cohort. The first objective was a scoping review that was undertaken to evaluate existing literature for potential biomarkers for CKD and to identify gaps in literature. Key literature gaps identified included the lack of studies that focus on HT in the context of kidney disease and only one study on African individuals residing in Africa. In this work, two research studies were developed based on existing data from the African Research Kidney Disease (ARK) study, a well characterised population-based cohort study of black individuals from Agincourt in the rural Mpumalanga Province, South Africa. The second objective was a genomics study which aimed to examine the potential of using summary statistics from three discovery datasets to assess the predictive accuracy of polygenic scores (PGSs) for CKD and kidney function markers. Limited transferability was observed, explaining <1% of the variability in kidney disease markers in this African cohort. A PGS model derived from the transethnic cohort for estimated glomerular filtration rate (eGFR) explained the highest variability (0.8%) in African individuals and was significantly associated with HT (P<0.001), diabetes (P=0.007), and HIV (P=0.001). The third objective was a proteomics study which aimed to compare proteomic profiles of cases with both HT and albuminuria to controls (neither condition) to identify proteins and pathways involved in hypertension- associated albuminuria. Pathways including immune system (q=1.4x10-45) and innate immune system (q=1.1x10-32) were linked with hypertension-associated albuminuria. Proteins including angiotensinogen, apolipoprotein L1, and uromodulin had the highest disease scores (76–100% confidence). A machine learning approach was able to identify a set of 20 proteins that contributed to classifying disease status (ie, hypertension-associated albuminuria). Page | VI The assessment of PGSs for kidney function markers contribute to understanding of CKD genetic risk prediction in Africa, while the proteomics research added new knowledge to understanding the role of proteins and pathways involved in hypertension-associated albuminuria in Africa. This research addresses the gap of a lack of ‘omics research in resident African populations. It also contributes to the understanding of risk prediction for CKD and identifies potential proteomic markers for hypertension-associated albuminuria that may inform the development of personalised treatment strategies in Africa.en© 2024 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg.UCTDAfrican genomicschronic kidney diseaseThesisUniversity of the Witwatersrand, JohannesburgSDG-3: Good health and well-being