PHARMACOGENOMICS FOR CHRONIC DISEASE MEDICINES IN AN AUSTRALIAN INDIGENOUS POPULATION

A JAYASHANKAR1,2, W ELIZABETH HOY3,4, BMCMORRAN5, V SCARIA6, S FOOTE5, S H NAGARAJ1,2,7

1Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia, 2School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia, 3NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane, Australia, 4Faculty of Medicine, The University of Queensland, Brisbane, Australia, 5John Curtin School of Medical Research, Australian National University, Canberra, Australia, 6CSIR Institute of Genomics and Integrative Biology, New Delhi, India, 7Translational Research Institute, Brisbane, Australia

Aim: To use whole genome sequencing (WGS) to define the pharmacogenomic landscape for chronic disease medicines in a remote Australian Aboriginal group.
Background: Rates of chronic disease are greatly increased among Aboriginal people in Australia’s Northern Territory, with most adults prescribed several medications. Pharmacogenomics (PGx) helps to reduce polypharmacy-associated risks and improve health outcomes for patients with chronic disease.  We assessed the chronic disease pharmacogenomic landscape in Tiwi Aboriginal people, building on the most comprehensive chronic disease profiling performed in any Aboriginal community, the longest follow up, and documentation of treatment and prevention responsiveness and of endpoints.
Methods: ANNOVAR was used to annotate variants from 188 whole genomes and we filtered well characterised pharmacogenomic variants (1A, 1B) in PharmGKB database and deleterious variants in known pharmacogenes (n=905). Star-allele designation of 50 pharmacogenes indicating metabolizer phenotype was predicted using Stargazer software. Significance of PGx variant allele frequencies were tested with PLINK and SKAT software. Dosing guidelines were obtained from Clinical Pharmacogenetics Implementation Consortium (CPIC).
Results: We observed 305,196 variants across 906 pharmacogenes, of which 395 were putative PGx variants. We also identified 23 high evidence PGx variants common in the Tiwi population that are associated with dosage, efficacy and toxicity of certain anti-hypertensive, anti-thrombotic and analgesic medications. These include Warfarin, Losartan, Clopidogrel and Omeprazole, which are metabolized by CYP2C9, C19, 3A5, 3A4 and D6 enzymes. The increased frequencies of poor and intermediate phenotypes in CYP2C9(PM:19%,IM:44%), CYP2C19 (PM:18%,IM:44%) genes are likely to affect the efficacy and toxicity of these drugs.
Conclusion: These findings have potential for clinical translation. The applicability CPIC guidelines to Indigenous Australians require culturally safe and community-led adoption strategies.


Biography:
Professor Wendy Elizabeth Hoy AO is a Fellow of the Australian Academy of Science (FAA), the Director of the Centre for Chronic Disease at the University of Queensland, Australia, and was appointed an Officer of the Order of Australia (AO) in 2010 and elected as a member of the Australian Academy of Sciences in 2015. Hoy’s research has involved developing new types of kidney imaging and improving health and lives for indigenous populations, in Australia, Sri Lanka and the USA

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