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Pharmacogenomic analysis of a genetically distinct Indigenous population

The Pharmacogenomics Journal volume 22, pages 100–108 (2022)Cite this article

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Abstract

Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.

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Fig. 1: PCA plot of Tiwi, Andaman, and 1KGP3 populations PCA plots shown correspond to 713,220 markers and 2631 individuals (10 Andamanese, 187 Tiwi, and 2504 individuals from the 1KGP3 dataset).
Fig. 2: Predicted phenotype distributions in pharmaco-genes.
Fig. 3: Distributions of CYP2C19, CYP2C9, and CYP2D6 star-allele frequencies among global populations.
Fig. 4: High-evidence PGx variants in Tiwi genomes PGx variants (PharmGKB levels 1A, 1B, and PGx-SV) present in the Tiwi genomes with allele frequencies ≥0.1 and significantly different from 1KGP3_ALL (Adj P value ≤ 0.05).

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Acknowledgements

The authors would like to acknowledge the following people: Barry Ullungurra for his help as the key contact person with the Tiwi Islanders; Bev Mcleod and Ceri Flowers for their project management and sample and data collection; Maria Scarlett for her considerable advice and guidance on the ethics of this project; and Beverley Hayhurst for the original sample collection and most notably the study participants and the Tiwi Land Council for their time and ongoing support for this project.

Funding

Funding for this research was supported by grants from the National Health and Medical Research Council (GNT1024207) and MRFF Genomics Health Futures Mission (76757). The Centre for Chronic Disease, The University of Queensland, is supported in-part by the NHMRC, Chronic Kidney Disease Centre of Research Excellence, 2016–2020 (APP1079502). The National Centre for Indigenous Genomics’ genome sequencing programme is supported by grants from the Australian Genomics Health Alliance, the Australian Research Data Commons (ARDC), Bio-platforms Australia (BPA), the Canberra Medical Society, the National Computational Infrastructure (NCI) through their ANU and National Merit Allocation Schemes, and the NHMRC (GNT1143734).

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Authors and Affiliations

  1. Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, 4059, Australia

    Arvind Jaya Shankar, Sudhir Jadhao & Shivashankar H. Nagaraj

  2. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, 4059, Australia

    Arvind Jaya Shankar, Sudhir Jadhao & Shivashankar H. Nagaraj

  3. Faculty of Medicine, University of Queensland, Brisbane, QLD, 4072, Australia

    Wendy Hoy

  4. John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2600, Australia

    Simon J. Foote & Brendan J. McMorran

  5. National Centre for Indigenous Genomics, Australian National University, Canberra, ACT, 2600, Australia

    Hardip R. Patel

  6. CSIR Institute of Genomics and Integrative Biology, Mathura Road, Delhi, 110 025, India

    Vinod Scaria

  7. Translational Research Institute, Queensland University of Technology, Brisbane, QLD, 4102, Australia

    Shivashankar H. Nagaraj

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Contributions

SHN led the project and oversaw the analysis. AJS designed and performed the research. AJS and SHN prepared the first draft of the manuscript. SJ assisted in curation and analysis of genome data. VS, HRP and BM contributed to the data analysis and refining the manuscript. WH, SJF provided critical intellectual comments during the manuscript writing and revisions. All authors have read and approved the final manuscript.

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Correspondence to Shivashankar H. Nagaraj.

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Jaya Shankar, A., Jadhao, S., Hoy, W. et al. Pharmacogenomic analysis of a genetically distinct Indigenous population. Pharmacogenomics J 22, 100–108 (2022). https://doi.org/10.1038/s41397-021-00262-4

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