Exploring Pharmacogenetic Factors Influencing Hydroxyurea Response in Tanzanian Sickle Cell Disease Patients: A Genomic Medicine Approach

Abstract

AbstractSickle cell disease (SCD) continues to pose a significant public health challenge, particularly in sub-Saharan Africa. Despite its discovery over a century ago, the progress in developing and accessing effective interventions has been notably restricted. Currently, hydroxyurea stands as the primary drug in widespread use, and has been associated with elevated levels of fetal hemoglobin (HbF) and enhanced clinical outcomes. Notably, a substantial proportion, up to 30%, of patients do not exhibit a positive response to hydroxyurea treatment. There is compelling evidence suggesting that genetic factors play a crucial role in influencing the effectiveness of hydroxyurea. In this study, we present findings on the investigation of genetic variants influencing hydroxyurea response in 13 genetic loci associated with HbF synthesis and hydroxyurea drug metabolism focusing onMYB,HBB,HBG1,HBG2,BCL11A,KLF10,HAO2,NOS1,ARG2,SAR1A,CYP2C9,CYP2E1. We report remarkable genetic associations withCYP2C9,CYP2E1, KLF10,BCL11A,ARG2,HBG1,SAR1A,MYB, andNOS1loci with hydroxyurea response. We also highlight associated pathway’s enrichment and gene-gene interactions analysis in the context of hydroxyurea treatment response.