Pharmacogenomic analysis of a genetically distinct Indigenous population

Shankar, Arvind Jaya; Jadhao, Sudhir; Hoy, Wendy E.; Foote, Simon J.; Patel, Hardip R.; Scaria, Vinod; McMorran, Brendan J.; Nagaraj, Shivashankar H.

doi:10.1038/s41397-021-00262-4

Cited by 5 publications

(6 citation statements)

References 62 publications

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“…We and others have characterized the blood group profiles (Jadhao et al, 2022), genetic susceptibility to chronic kidney disease (Thomson et al, 2019) and a variant affecting platelet function (Ningtyas et al, 2020) in this population. This study is the first to comprehensively investigate clinically actionable pharmacogenes in the Tiwi people, contributing novel, important findings and further validating the results of a previous attempt to characterise Tiwi PGx profiles (Jaya Shankar et al, 2022).…”

Section: Discussionsupporting

confidence: 67%

“…We have previously shown that Tiwi people are genetically distinct using a separately collected cohort of 249 individuals ( Thomson et al, 2019 ) and a subset of the cohort used in this study consisting of 187 individuals ( Jaya Shankar et al, 2022 ). The findings were recapitulated in the current study through PCA analysis of a larger cohort consisting of 469 individuals after QC ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…We previously conducted one of the earliest Indigenous Australian PGx studies evaluating pharmacological variability in this population ( Jaya Shankar et al, 2022 ). Building on this recent report, we herein carried out a comprehensive PGx analysis of a founder Indigenous population in Australia, harboring a unique genetic architecture.…”

Section: Introductionmentioning

confidence: 99%

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The pharmacogenomic landscape of an Indigenous Australian population

et al. 2023

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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.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

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The pharmacogenomic landscape of an Indigenous Australian population

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“…These results were corroborated by a large aggregate study in Scandinavia, which confirmed *3 frequencies of 6% in a large sample of 3,503 individuals from Norway, Sweden, Denmark and Finland [ 25 ]. Most pronounced differences were observed between the indigenous Tiwi population and groups of European ancestry in Australia with frequencies of CYP2C9*2 (12.8% and 0% in Europeans and Tiwi, respectively) and CYP2C9*3 (6.9% and 36%, respectively) differing by more than fivefold [ 26 ]. Genetic variability profiles of Tiwi were moreover drastically different from indigenous Polynesian and Maori populations.…”

Section: Discussionmentioning

confidence: 99%

Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

et al. 2023

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Background Genetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking. Results Frequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs. Conclusions This study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

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“…The medical world now stands at the dawn of the genomic era and eagerly awaits the advent of genuine personalised medicine. As an example of how this might work, we point to the study by Shankar et al (2022) . Future prospects for a genome-level One Health approach are well illustrated by their recent pharmacogenomic study involving Tiwi Islanders (from Northern Territory, Australia).…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-based classifications and medical genetics: One Health approaches from a Western Pacific perspective

2022

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A new era presently dawns for medical genetics featuring individualised whole genome sequencing and promising personalised medical genetics. Accordingly, we direct readers attention to the continuing value of allele frequency data from Genome-Wide Association Surveys (GWAS) and single gene surveys in well-defined ethnic populations as a guide for best practice in diagnosis, therapy, and prescription. Supporting evidence is drawn from our experiences working with Austronesian volunteer subjects across the Western Pacific. In general, these studies show that their gene pool has been shaped by natural selection and become highly diverged from those of Europeans and Asians. These uniquely evolved patterns of genetic variation underlie contrasting schedules of disease incidence and drug response. Thus, recognition of historical bonds of kinship among Austronesian population groups across the Asia Pacific has distinct public health advantages from a One Health perspective. Other than diseases that are common among them like gout and diabetes, Austronesian populations face a wide range of climate-dependent infectious diseases including vector-borne pathogens as they are now scattered across the Pacific and Indian Oceans. However, we caution that the value of genetic survey data in Austronesians (and other groups too) is critically dependent on the accuracy of attached descriptive information in associated metadata, including ethnicity and admixture.

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Pharmacogenomic analysis of a genetically distinct Indigenous population

Cited by 5 publications

References 62 publications

The pharmacogenomic landscape of an Indigenous Australian population

The pharmacogenomic landscape of an Indigenous Australian population

Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

Ethnicity-based classifications and medical genetics: One Health approaches from a Western Pacific perspective

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