Clonal Haematopoiesis of Indeterminate Potential in Adult Nigerians: Prevalence, Mutational Landscape, and Cardiovascular Risk Associations Across Geopolitical Zones

This dissertation characterises the prevalence, mutational landscape, and cardiovascular risk associations of clonal haematopoiesis of indeterminate potential (CHIP) in a large multi-centre cohort of adult Nigerians spanning all six geopolitical zones, providing the first Nigerian CHIP genomics reference dataset and an original analytical framework for its clinical implications. CHIP, the age-associated somatic expansion of haematopoietic clones carrying driver mutations, has been linked to atherosclerosis, heart failure, and haematological malignancy risk in European and American cohorts, but its epidemiology in African ancestry populations is almost entirely uncharacterised. Using an observational design, peripheral blood from 1,200 adults aged 45 to 80 years without haematological malignancy was collected from 12 tertiary hospitals across the six geopolitical zones. Error-corrected sequencing of a 54-gene CHIP panel was performed at variant allele frequency sensitivity of 0.5 percent. Cardiovascular phenotyping used echocardiography and carotid intima-media thickness measurement. CHIP prevalence increased from 4.2 percent in those aged 45 to 54 to 18.7 percent in those above 75. DNMT3A and TET2 were the most frequently mutated genes, consistent with other populations, but the allelic spectrum differed from European cohorts, with three novel driver variants of uncertain significance identified and functionally annotated. High variant allele frequency CHIP above 10 percent was associated with a 2.1-fold increase in cardiovascular disease risk after adjustment. The dissertation proposes an original Nigerian CHIP Clinical Risk Model integrating VAF, mutation type, and cardiovascular risk factors. Keywords: clonal haematopoiesis, CHIP, cardiovascular risk, somatic mutations, Nigerian adults.