Regulatory Variant Analysis in the BCL11A Gene and Its Role in Foetal Haemoglobin Variation in SCD Patients in Kaduna State

Foetal haemoglobin (HbF) is a clinically significant modifier of sickle cell disease severity, and individuals with higher HbF levels typically experience milder disease. The BCL11A transcription factor gene is the principal repressor of HbF synthesis, and regulatory variants in its erythroid enhancer region are major quantitative trait loci for HbF levels identified in multiple populations. This study characterised regulatory variants in the BCL11A erythroid enhancer and examined their association with HbF levels in sickle cell disease patients in Kaduna State, North West Nigeria. One hundred and fifty HbSS patients were recruited from specialist SCD clinics at Barau Dikko Teaching Hospital, Kaduna. HbF levels were measured by high-performance liquid chromatography (HPLC). Genomic DNA was sequenced across the BCL11A erythroid enhancer region (+55, +58, +62 kb sub-elements) by targeted Sanger sequencing. Variant association with HbF was assessed by linear regression adjusting for age, sex, and hydroxyurea use. The rs1427407 and rs7606173 variants within the +62 kb sub-element were significantly associated with HbF level variation. Patients with HbF-raising genotypes at both loci had substantially higher mean HbF. These findings support BCL11A enhancer variant status as a genetic predictor of HbF levels and SCD severity in North West Nigeria. Keywords: BCL11A, foetal haemoglobin, regulatory variants, sickle cell disease, Kaduna State