Collin Nzunda

Muhimbili University of Health and Allied Sciences

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Julie Makani

Muhimbili University of Health and Allied Sciences

Florence Urio

Muhimbili University of Health and Allied Sciences

Frida Kaywanga

Muhimbili University of Health and Allied Sciences

Doreen Ngowi

Muhimbili University of Health and Allied Sciences

Julieth Johansen

Muhimbili University of Health and Allied Sciences

Clara Chamba

Muhimbili University of Health and Allied Sciences

Josephine Mgaya

Muhimbili University of Health and Allied Sciences

Siana Nkya

Muhimbili University of Health and Allied Sciences

Heavenlight Christopher

Muhimbili University of Health and Allied Sciences

Raphael Zozimus Sangeda

Muhimbili University of Health and Allied Sciences

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Muhimbili University of Health and Allied Sciences

Catholic University of Health and Allied Sciences

University of Cape Town

Muhimbili National Hospital

African Malaria Network Trust

Clinical Research Institute

King's College London

Northumbria University

University of Pittsburgh

Tanzania Food and Nutrition Center

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Towards genomic medicine: a tailored next-generation sequencing panel for hydroxyurea pharmacogenomics in Tanzania

BMC Medical Genomics (2024)

Siana Nkya Collin Nzunda Emmanuel Saukiwa Frida Kaywanga Eliud Buberwa

Abstract Background Pharmacogenomics of hydroxyurea is an important aspect in the management of sickle cell disease (SCD), especially in the era of genomic medicine. Genetic variations in loci associated with HbF induction and drug metabolism are prime targets for hydroxyurea (HU) pharmacogenomics, as these can significantly impact the therapeutic efficacy and safety of HU in SCD patients. Methods This study involved designing of a custom panel targeting BCL11A, ARG2, HBB, HBG1, WAC, HBG2, HAO2, MYB, SAR1A, KLF10, CYP2C9, CYP2E1 and NOS1 as potential HU pharmacogenomics targets. These genes were selected based on their known roles in HbF induction and HU metabolism. The panel was designed using the Illumina Design Studio (Illumina, San Diego, CA, USA) and achieved a total coverage of 96% of all genomic targets over a span of 51.6 kilobases (kb). This custom panel was then sequenced using the Illumina MiSeq platform to ensure high coverage and accuracy. Results We are reporting a successfully designed Illumina (MiSeq) HU pharmacogenomics custom panel encompassing 51.6 kilobases. The designed panel achieved greater than 1000x amplicon coverage which is sufficient for genomic analysis. Conclusions This study provides a valuable tool for research in HU pharmacogenomics, especially in Africa where SCD is highly prevalent, and personalized medicine approaches are crucial for improving patient outcomes. The custom-designed Illumina (MiSeq) panel, with its extensive coverage and high sequencing depth, provides a robust platform for studying genetic variations associated with HU response. This panel can contribute to the development of tailored therapeutic strategies, ultimately enhancing the management of SCD through more effective and safer use of hydroxyurea.

Pharmacogenomics

Personalized Medicine

10.1186/s12920-024-01924-5

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Genomics of fetal haemoglobin: a targeted approach for reticulocyte transcriptome study

Research Square (Research Square) (2023)

Siana Nkya Frida Kaywanga Collin Nzunda Salmaan Karim David Solomon

Abstract Background: Fetal haemoglobin (HbF) remains a major sickle cell disease modifier. The mechanism of HbF synthesis has been studied for several decades with the intention of increasing interventions for sickle cell disease (SCD), including drugs. However, the complex mechanism of HbF synthesis is influenced by multiple genetic factors interacting with environmental factors. In order to capture useful genetic information, especially with limited resources, one has to carefully design the study. This includes choosing the relevant participants, the correct phenotyping, the choice of samples, and the right genomic assays. This paper describes the approach undertaken as part of preparations for a reticulocyte transcriptome study intended to discover genes associated with HbF decline in newborns in Tanzania. Results: Of the 152 newborns enrolled in the larger study, 40 babies were selected for the reticulocyte transcriptome study based on their HbF levels at birth and later stage of life. Of these, 30 individuals were included under the category of high HbF levels ranging from 72.6-90% and the remaining 10 under the category of low HbF levels ranging from 5.9 - 10.3%. The reticulocyte enrichment recovery purity ranged from 85% - 97%. The total RNA concentrations obtained were >250 ng total RNA, with the average purity of 1.9 (A 260/280) respectively. The total concentration obtained was sufficient for the transcriptome and other downstream assays. Conclusion: We have documented important steps and factors to consider in identifying the relevant participants and required laboratory sample processes prior to the final stage, which involves total reticulocyte RNA sequencing.

Reticulocyte

10.21203/rs.3.rs-3061395/v1

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Early-Life Clinical and Hematological Profiles: A Comparative Study of Children with and Without Sickle Cell Disease in the First Three Years of Life

Siana Nkya Isihaka Mahawi Rehema Shungu Collin Nzunda Frida Kaywanga

10.2139/ssrn.5030155

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

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Siana Nkya Collin Nzunda Emmanuel Saukiwa Frida Kaywanga Eliud Buchard

Abstract Sickle 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 on MYB , HBB , HBG1 , HBG2 , BCL11A , KLF10 , HAO2 , NOS1 , ARG2 , SAR1A , CYP2C9 , CYP2E1 . We report remarkable genetic associations with CYP2C9 , CYP2E1, KLF10 , BCL11A , ARG2 , HBG1 , SAR1A , MYB , and NOS1 loci with hydroxyurea response. We also highlight associated pathway’s enrichment and gene-gene interactions analysis in the context of hydroxyurea treatment response.

Drug response

10.1101/2024.05.23.595488

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Towards Genomic Medicine: A Tailored Next-Generation Sequencing Panel for Hydroxyurea Pharmacogenomics in Tanzania

Research Square (Research Square) (2023)

Siana Nkya Collin Nzunda Emmanuel Saukiwa Frida Kaywanga Eliud Buchard

Abstract Pharmacogenomics of hydroxyurea is an important aspect in the management of sickle cell disease (SCD), especially in the era of genomic medicine. Genetic variations in loci associated with HbF induction and drug metabolism are prime targets for hydroxyurea (HU) pharmacogenomics. This study investigated genetic variations in BCL11A, ARG2, HBB, HBG1, WAC, HBG2, HAO2, MYB, SAR1A, KLF10, CYP2C9, CYP2E1 and NOS1 as potential HU pharmacogenomics targets. The panel was designed using the Illumina Design Studio (Illumina, San Diego, CA, USA) and achieved a total coverage of 96% of all genomic targets over a span of 51.6 kilobases (kb). We are reporting a successfully designed Illumina (MiSeq) HU pharmacogenomics custom panel encompassing 51.6 kilobases. The designed panel achieved greater than 1000x amplicon coverage which is which is sufficient for genomic analysis. Therefore, this study provides a valuable tool for research in HU pharmacogenomics, especially in Africa.

Pharmacogenomics

Personalized Medicine

10.21203/rs.3.rs-3235315/v1

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

Siana Nkya Collin Nzunda Emmanuel Josephat Frida Kaywanga Eliud Buchard

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Pharmacogenomics

Personalized Medicine

Drug response

10.2139/ssrn.4714409

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