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Exploring pharmacogenetic factors influencing hydroxyurea response in tanzanian sickle cell disease patients: a genomic medicine approach

The Pharmacogenomics Journal volume 25, Article number: 11 (2025) Cite this article

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Abstract

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.

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Fig. 1: Haematological profiles of poor and good responders to hydroxyurea treatment.
Fig. 2: Distribution of pathogenic SNPs across the targeted genetic variants in the studied population and other ethnic groups.
Fig. 3: PCA plot of Hydroxyurea associated population structure across world-wide ethnicities.
Fig. 4: Gene-gene interaction network of genes harbouring the most deleterious variants.

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Data availability

Genomic sequencing data generated in this study have been submitted to the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/) under accession number PRJNA1114738. The original contributions presented in the study are included in the article/supplementary material, further inquiries contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

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Acknowledgements

The Sickle cell Program and the Haematology Clinical and Research Laboratory of the Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences is highly appreciated for the cooperation shown during the whole time of study.

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Authors and Affiliations

  1. Department of Haematology and Blood Transfusion,, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    Siana Nkya, Collin Nzunda, Frida Kaywanga, Eliud Buchard, David Solomon, Heavenlight Christopher, Doreen Ngowi, Julieth Johansen, Clara Chamba & Julie Makani

  2. Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    Siana Nkya, Emmanuel Saukiwa, Florence Urio, Salman Karim & Mohamed Zahir Alimohamed

  3. Tanzania Human Genetics Organisation, Dar es Salaam, Tanzania

    Siana Nkya, Frida Kaywanga, Mohamed Zahir Alimohamed, Raphael Z. Sangeda & Julie Makani

  4. Sickle Cell Program, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    Siana Nkya, Frida Kaywanga, Josephine Mgaya, Mohamed Zahir Alimohamed, Raphael Z. Sangeda & Julie Makani

  5. Muhimbili National Hospital, Dar es Salaam, Tanzania

    Christina Kindole & Mbonea Yonazi

  6. Department Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    Raphael Z. Sangeda

  7. Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa

    Collet Dandara

  8. Pharmacogenomics Research and Translation Unit, South African Medical Research Council, Cape Town, South Africa

    Collet Dandara

  9. Vascular Medicine Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Enrico Novelli

  10. Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle, Tyne and Wear, UK

    Emile R. Chimusa

  11. SickleInAfrica, Cape Town, South Africa

    Julie Makani

  12. Imperial College London, London, UK

    Julie Makani

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Contributions

SN contributed to conceptualization, funding acquisition, supervision, and project administration. CN, ERC, EB, ES, FK, HC, and MZ were involved in data curation, formal analysis, investigation, methodology, and software development. ERC, CN, SN, and CD contributed to writing, review and editing, conceptualization, methodology, supervision, validation, resources, and visualization. DS, DN, JJ, FU, JM, SK, RS, CC, JM, CK, MY, and EN critically reviewed the data and edited the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Collin Nzunda.

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The authors declare no competing interests.

Ethical approval and consent to participate

This study received ethical approval from the Institutional Review Board at Muhimbili University of Health and Allied Science, number MUHAS-REC-2018-078. Both verbal and written consent were obtained from mothers to agree their babies to participate in this study. Informed consent to participate was obtained from the parents or legal guardians of any participant under the age of 16. Consent forms were signed by the mothers or legal guardians who agreed to their children to participate after the research assistant educated them.

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Nkya, S., Nzunda, C., Saukiwa, E. et al. Exploring pharmacogenetic factors influencing hydroxyurea response in tanzanian sickle cell disease patients: a genomic medicine approach. Pharmacogenomics J 25, 11 (2025). https://doi.org/10.1038/s41397-025-00372-3

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