Nkya Siana, Nzunda Collin, Saukiwa Emmanuel, Kaywanga Frida, Buchard Eliud, Solomon David, Christopher Heavenlight, Ngowi Doreen, Johansen Julieth, Urio Florence, Mgaya Josephine, Kindole Christina, Yonazi Mbonea, Karim Salman, Alimohamed Mohamed Zahir, Sangeda Raphael Z, Chamba Clara, Dandara Collet, Novelli Enrico, Chimusa Emile R, Makani Julie
Department of Haematology and Blood Transfusion,, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Pharmacogenomics J. 2025 Apr 23;25(3):11. doi: 10.1038/s41397-025-00372-3.
In sub-Saharan Africa, sickle cell disease (SCD) remains a significant public health challenge. Despite the discovery of SCD over a century ago, progress in developing and accessing effective treatments has been limited. Hydroxyurea is the primary drug used for managing SCD and associated with improving clinical outcomes. However, up to 30% of patients do not respond to hydroxyurea, likely due to genetic factors. This study involved 148 individuals with SCD investigated the association of hydroxyurea response with genetic variants across 13 loci associated with HbF synthesis and drug metabolism, focusing on MYB, HBB, HBG1, HBG2, BCL11A, KLF10, HAO2, NOS1, ARG2, SAR1A, CYP2C9, and CYP2E1. Significant associations with hydroxyurea response were identified in CYP2C9, CYP2E1, KLF10, BCL11A, ARG2, HBG1, SAR1A, MYB, and NOS1 loci. Furthermore, pathway enrichment and gene-gene interaction analyses provide deeper insights into the genetic mechanisms underlying hydroxyurea treatment response, highlighting potential avenues for personalized therapy in SCD management.
在撒哈拉以南非洲地区，镰状细胞病（SCD）仍然是一项重大的公共卫生挑战。尽管一个多世纪前就发现了SCD，但在开发和获取有效治疗方法方面的进展一直有限。羟基脲是用于治疗SCD的主要药物，与改善临床结果相关。然而，高达30%的患者对羟基脲无反应，这可能是由于遗传因素。本研究纳入了148名SCD患者，调查了羟基脲反应与13个与HbF合成和药物代谢相关位点的基因变异之间的关联，重点关注MYB、HBB、HBG1、HBG2、BCL11A、KLF10、HAO2、NOS1、ARG2、SAR1A、CYP2C9和CYP2E1。在CYP2C9、CYP2E1、KLF10、BCL11A、ARG2、HBG1、SAR1A、MYB和NOS1位点发现了与羟基脲反应的显著关联。此外，通路富集和基因-基因相互作用分析为羟基脲治疗反应的遗传机制提供了更深入的见解，突出了SCD管理中个性化治疗的潜在途径。
