Proteogenomic Discovery and Functional Validation of Novel Sickle Cell Disease Severity Biomarkers in a Longitudinal Cohort from South West Nigeria

Sickle cell disease severity is highly heterogeneous even among individuals with the same HbSS genotype, reflecting complex genetic modifier landscapes and environmental influences that current clinical biomarkers inadequately capture, limiting individualised care and preventive intervention. This research applies proteogenomics to discover and functionally validate novel SCD severity biomarkers in a longitudinal cohort of HbSS patients at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Osun State, South West Nigeria. A five-year longitudinal study will follow 200 HbSS adults with quarterly blood and urine collection during both steady state and vaso-occlusive crisis episodes. Plasma proteomics by data-independent acquisition mass spectrometry will identify proteins differentially expressed across severity trajectories. Genome-wide genotyping will identify genetic modifiers including HbF-regulating loci, HMOX1, and complement pathway variants. Multi-omics integration using DepMap-adapted frameworks will construct protein-genotype interaction networks. Candidate biomarkers showing consistent association with crisis frequency, hospitalisation, and organ damage indices will be prioritised for targeted assay development and validation. Functional validation of top candidates will include cell-based endothelial adhesion and oxidative stress assays. A computational severity prediction model incorporating top biomarkers will be trained and cross-validated. Original contributions include the most comprehensive proteogenomic SCD dataset from West Africa, a novel theoretical model of proteome-genotype interaction in SCD severity determination, and validated candidate biomarkers ready for clinical assay translation. Findings will enable precision SCD care and targeted preventive therapy in Nigeria's highest-burden disease population. Keywords: sickle cell disease, proteogenomics, severity biomarkers, HbSS, longitudinal cohort