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Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP)

The Pharmacogenomics Journal volume 23, pages 82–88 (2023)Cite this article

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Abstract

Background

Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins’s narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients’ therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness.

Method and results

A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation.

Conclusion

The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.

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Data availability

The list of the variants and their allele frequencies are provided in the supplementary of this article. Additional data can be accessed from https://figshare.com/articles/dataset/SWAP_Files/21948221

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Acknowledgements

We would like to thank the Saudi Biobank department for their help in initial processing and handling the biological samples; also, we thank the Medical Genomics Research Departments for conducting the NGS experiments. Special thanks to the patients who volunteered to be part of this study.

Funding

This work was funded by King Abdullah International Medical Research Center (KAIMRC), research grant number RC12/163.

Author information

Authors and Affiliations

  1. Pharmaceutical Care Services, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Maha Al Ammari, Khalid Al Sulaiman, Nada S. Almakhlafi, Anoud Al Humoud, Mohammed Waheeby, Munee Balla & Asma Al Shehri

  2. Medical Genomics Research Department, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Bader Almuzzaini

  3. King Abdullah International Medical Research Center (KAIMRC), PO Box 22490, 11426, Riyadh, Saudi Arabia

    Khalid Al Sulaiman

  4. College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

    Khalid Al Sulaiman

  5. Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia

    Khalid Al Sulaiman

  6. Department of Pathology and laboratory, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia

    Mohammed AlBalwi

  7. Research Office, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia

    Khizra Sultana

  8. Health Sciences Research Center, King Abdullah Bin Abdulaziz University Hospital, Princess Nourah bint Abdulrahman University, Riyadh, Kingdom of Saudi Arabia

    Ibrahim B. Alabdulkareem

  9. Saudi Food and Drug Authority, Drug Sector, Riyadh, Saudi Arabia

    Adel Alharf & Jahad Alghamdi

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Contributions

JA, MAA, MAB, and IBA, contributed to study concept and design; JA, KS, NSA, and AAA acquired and reviewed clinical data; JA conducted the bioinformatics and statistical analyses; JA, MAA, and BA performed the data interpretation; JA, MAA, BA, KS and KAS drafted manuscript. All authors revise and review the manuscript.

Corresponding author

Correspondence to Jahad Alghamdi.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential competing interest. The views expressed in this paper are those of the author(s) and DO NOT necessarily reflect those of their affiliated organization or its stakeholders. Guaranteeing the accuracy and the validity of the data is a sole responsibility of the research team.

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Ammari, M.A., Almuzzaini, B., Al Sulaiman, K. et al. Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP). Pharmacogenomics J 23, 82–88 (2023). https://doi.org/10.1038/s41397-023-00300-3

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