The pharmacogenomic landscape of an Indigenous Australian population

Frontiers in Pharmacology

Pharmacology

Sudhir Jadhao¹  Sumudu Rangika Samarasinghe¹  Shivashankar H. Nagaraj²  Henk-Jan Guchelaar³  Wendy Hoy⁴  Brendan J. McMorran⁵ 

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

关键词: pharmacogenomics;    pharmacogenetics;    adverse drug reactions;    population genomics;    Indigenous Australians;    variable drug response;   

DOI  :  10.3389/fphar.2023.1180640

 received in 2023-03-06, accepted in 2023-04-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Samarasinghe, Hoy, Jadhao, McMorran, Guchelaar and Nagaraj.