Genetic and Biochemical Determinants of Differential Response to Antihypertensive Therapy in Nigerian Hypertensive Patients: A Pharmacogenomic Approach

Antihypertensive drug response variability is clinically significant in Nigerian patients, where multiple genetic and biochemical factors converge to produce differential therapeutic outcomes, yet pharmacogenomic characterisation of this variability in the Nigerian genetic context remains in its infancy compared to Asian and European populations. This dissertation investigates the genetic and biochemical determinants of differential antihypertensive drug response in Nigerian patients using a pharmacogenomic approach, making original contributions to precision hypertension management in the African context. A prospective pharmacogenomic study enrolled seven hundred and fifty newly diagnosed hypertensive patients at three teaching hospitals in Abuja, Kaduna, and Ibadan. Patients were randomized to four initial antihypertensive drug classes: calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, and thiazide diuretics. Blood pressure response was assessed at four, eight, and twelve weeks. Biochemical response indicators including renin activity, aldosterone, angiotensin-converting enzyme activity, endothelin-1, urinary sodium, and potassium were measured at baseline and at therapeutic response assessment. Genome-wide pharmacogenomic profiling was performed using the H3Africa SNP genotyping array, with candidate gene and GWAS analyses examining variants in ACE, CYP11B2, AGTR1, CYP3A5, ADRB1, SLC12A3, and CACNA1C. Machine learning integration of genetic, biochemical, and clinical variables constructed a differential response prediction model. Significant novel pharmacogenomic associations were identified, including two African-specific variants in the CYP11B2 aldosterone synthase promoter strongly predicting thiazide response. A biochemical phenotyping algorithm combining renin activity and aldosterone-to-renin ratio significantly predicted drug class differential response independent of genetics. The dissertation proposes an original Nigerian hypertension pharmacogenomic decision framework. Keywords: pharmacogenomics, antihypertensive therapy, drug response, Nigerian patients, precision medicine.