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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.

Background: Hepatocellular carcinoma (HCC) is becoming a challenging global health concern with Asian and African countries carrying the highest burden of it. The rising prevalence of non-alcoholic steatohepatitis (NASH) associated HCC is linked with unhealthy dietary patterns and sedentary life styles. In addition, genetic predisposition may play a critical role in developing NASH-related HCC. Previous studies have identified that variants in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are significantly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. But there are no published reports on their impact on Sri Lankan NASH-HCC patients. Methods: We conducted an exploratory study to evaluate the prevalence of five single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, PNPLA3rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC samples that were collected at a clinical setting and analyzed using statistical modelling to explore the impact of each SNP with tumor prognostic factors. Results: We observed high frequencies in four out of five polymorphisms, namely PNPLA3 rs738409 (0.79, 95%CI 0.650-0.895), PNPLA3 rs2281135 (0.77, 95%CI 0.627-0.880), PNPLA3 rs2294918 (0.9, 95%CI 0.773-0.965) and MBOAT7rs641738 (0.85, 95%CI 0.722-0.939) among Sri Lankan NASH-HCC patients. Our analyses further demonstrated significant associations of PNPLA3variants with a total tumor diameter of NASH-HCC patients while PNPLA3 rs2294918 and MBOAT7 rs641738 had significant associations with single-nodular HCC. Of the five SNPs, we observed a strong correlation between PNPLA3 rs738409 and PNPLA3 rs2294918 through pairwise linkage disequilibrium (LD) analysis. Conclusion: Observed high frequencies of risk alleles among genotyped SNPs warrants the possibility of genetic predisposition as a risk factor for NASH-related HCC in the Sri Lankan setting.

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