The pharmacogenomic landscape of an Indigenous Australian population

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.

Commentary: The pharmacogenomic landscape of an Indigenous Australian population

“…Caucasian individuals who carry these variants typically have a deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, the critical enzyme involved in the metabolism of fluoropyrimidine chemotherapies 5-fluorouracil and capecitabine, and can develop significant and life-threatening toxicity on exposure to these medications ( Froehlich et al, 2015 ). Interestingly, of the 160+ known DPYD variants only seven distinct DPYD variants were identified within this Tiwi cohort; six variants deemed ‘normal metabolisers’ and c.1236G>A which is known to be clinically significant ( Amstutz et al, 2018 ; Varughese et al, 2020 ; Samarasinghe et al, 2023 ). It is very significant that none of the 473 individuals screened carried c.1905 + 1G>A, c.1679T>G, c.2846A>T variants.…”

“…Samarasinghe et al conducted an analysis utilising whole genome sequencing on blood samples from 473 Tiwi Indigenous people looking specifically at the allele frequency of Very Important Pharmacogenes (VIP), as determined by PharmKGB ( pharmkgb.org ) ( Samarasinghe et al, 2023 ). Our specific interest relates to the dihydropyrimidine dehydrogenase ( DPYD ) and uridine diphosphate-glucuronosyltransferase isoform 1A1 ( UGT1A1 ) gene data.…”

“… Tiwi data from Samarasinghe et al (2023) . Population data from gnomAD v4.0.0 ( gnomad.broadinstitute.org ).…”

“…UGT1A1 was also sequenced by Samarasinghe et al in relation to the metabolism of antiretroviral Atazanavir ( Samarasinghe et al, 2023 ). This gene holds clinical significance in the administration of irinotecan chemotherapy ( Iyer et al, 1998 ).…”

“…UGT1A1 is the critical enzyme of irinotecan metabolism, and all heterozygote carriers within this cohort are ‘intermediate metabolisers’ according to pharmacogenetics guidelines for irinotecan prescribing ( Hulshof et al, 2022 ). Twenty-five heterozygote carriers of *6 and 18 heterozygous carriers of *28 (in compound with *80) were identified ( Varughese et al, 2020 ; Hulshof et al, 2022 ; Samarasinghe et al, 2023 ). One homozygote of 28* (+80*) was identified, inferring ‘poor metabolism’ of irinotecan.…”