The pharmacogenomic landscape of an Indigenous Australian population

Sumudu Rangika Samarasinghe; Wendy Hoy; Sudhir Jadhao; Brendan J McMorran; Henk-Jan Guchelaar; Shivashankar H Nagaraj

doi:10.3389/fphar.2023.1180640

The pharmacogenomic landscape of an Indigenous Australian population

Front Pharmacol. 2023 May 22:14:1180640. doi: 10.3389/fphar.2023.1180640. eCollection 2023.

Authors

Sumudu Rangika Samarasinghe¹, Wendy Hoy², Sudhir Jadhao¹, Brendan J McMorran³, Henk-Jan Guchelaar⁴, Shivashankar H Nagaraj^{1

5}

Affiliations

¹ Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, Australia.
² Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
³ John Curtin School of Medical Research, College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
⁴ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands.
⁵ Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.

Abstract

Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data. Results: We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing. Conclusion: The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations.

Keywords: Indigenous Australians; adverse drug reactions; pharmacogenetics; pharmacogenomics; population genomics; variable drug response.

Grants and 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), the Canberra Medical Society, the National Computational Infrastructure (NCI) through their ANU and National Merit Allocation Schemes, and the NHMRC (GNT1143734).