Genomic and Biochemical Correlates of Hydroxyurea Response Variability in Sickle Cell Disease Patients in Lagos and Abuja

Hydroxyurea is the most established disease-modifying therapy for sickle cell disease, primarily through induction of foetal haemoglobin, yet its clinical response varies substantially between patients through mechanisms that remain incompletely understood in African HbSS populations. This study investigates the genomic and biochemical determinants of hydroxyurea response variability in HbSS patients in Lagos (South West) and Abuja (North Central), Nigeria. A pharmacogenomic cohort design was employed, recruiting 150 HbSS patients who had been on standard-dose hydroxyurea for at least twelve months. Foetal haemoglobin level was the primary biochemical response variable. Genome-wide association analysis using an African ancestry SNP array identified loci associated with HbF induction response. Candidate polymorphisms in BCL11A, HMGA2, and HBS1L-MYB intergenic region were genotyped and analysed by logistic regression. Concurrent biochemical markers including BCL11A protein expression in erythroid progenitors, gamma-globin mRNA levels, and epigenetic marks at the HBG locus were characterised. Adherence was objectively assessed by hydroxyurea metabolite monitoring. This study generates novel pharmacogenomic data specific to the Nigerian HbSS population and will develop predictive biochemical models for personalised hydroxyurea therapy. Keywords: hydroxyurea, sickle cell disease, foetal haemoglobin, pharmacogenomics, BCL11A.