Pharmacogenomics and genetic diversity: Prospects at a tertiary care centre in Saudi ArabiaPharmacogenomics and genetic diversity: Prospects at a tertiary care centre in Saudi Arabia

Pharmacogenomics is the study of how a person’s genetic makeup affects their response (efficacy and/or safety) to drugs. This field aims to optimise drug dosing, considering interindividual variation to maximise efficacy and minimise toxicity. Efficacy rates have been reported to vary from 25 per cent-80 per cent across different individuals. Adverse drug reactions (ADRs) on the other hand account for 6.5 per cent of all hospital admissions, and > 15 per cent when people with multimorbidities are considered. Although genetics are not the only contributing factor, a large proportion of the variability can be attributed to them, as genetic variation in the coding areas of genes regulating drug responses is common in the human population. 

It is reported that approximately 50 per cent of drug prescriptions in the US are affected by actionable pharmacogenomic variations. In the UK, 58 per cent of patients were prescribed at least one drug with actionable pharmacogenes when observed over one year. The same UK database analysis showed that as people age, they are more likely to receive drug prescriptions and that >90 per cent of individuals aged 70 and above will receive at least one drug with pharmacogenomic guidance. 

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Pharmacogenomics aims to move away from the “one size/dose fits all” approach to a more personalised approach that is relevant to the patient's needs. Indeed, a large randomised clinical trial assessed the use of a 12-gene pharmacogenomic panel in reducing ARDs in 6944 eligible patients. A clinically significant reduction in the incidence of clinically relevant adverse drug reactions was observed in the study vs. control groups. 

Lack of diversity in genetic data 

More than 70 per cent of personalised medicine and PGx studies are conducted in North America (71 per cent), other regions include Asia (18 per cent), Australia, Europe, and South America. Moreover, it’s well known that individuals of diverse genetic ancestry are often underrepresented in the clinical trials behind drug development. These statistics raise a major concern about the utility of pharmacogenomics guidelines outside North America.  

Although pharmacogenomic implementation has shown promise in addressing inter-individual health disparities, many structural changes are still required to harbour the benefits of PGx at a larger scale. Going forward, a research priority in pharmacogenomics is enhancing the diversity and inclusion of genomic data, this is to ensure that (1) pharmacogenomics benefits can be implemented globally, and (2) pharmacogenomics does not perpetuate existing global health disparities. Multiple programmes have been launched to ameliorate the lack of diversity, this includes the Qatar Genome Program, H3Africa, GenomeAsia 100K Project, and others. 

The pharmacogenomics experience at KFSH&RC 

In Saudi Arabia, the only study published concerning pharmacogenomic variant frequencies was in 2022 using the database of the Saudi Human Genome Project. Nonetheless, a significant amount of work still needs to be done to generate generalisable data to be used for the Saudi population. The Centre for Genomic Medicine (CGM) at King Faisal Specialist Hospital and Research Center (KFSH&RC) has launched the first pharmacogenomic profiling service in the Kingdom and region. The test covers the most used medications as per hospital data that have actionable pharmacogenomic implications. Included medications and genes are as follows: Metoprolol (CYP2D6), Simvastatin (SLCO1B1), Atorvastatin (SLCO1B1), Clopidogrel (CYP2C19), Flecainide (CYP2D6) and Warfarin (VKORC1, CYP4F2, CYP2C9).  

The integration of pharmacogenomics into clinical practice constitutes a multifaceted procedure that extends beyond the mere presence of data and guidelines. This process necessitates the active involvement and collaboration of diverse stakeholders operating at various hierarchical levels. These stakeholders include leadership with a vested interest, pharmacy and laboratory personnel, informed healthcare providers, a robust Information Technology infrastructure, a dynamic scientific committee, financial contributors, and, most importantly, the engaged and informed patient population. 

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In our experience at KFSH&RC, we embarked on this substantial task by assembling a team comprising clinical scientists, clinical pharmacists, and physicians to actively participate in the implementation process. We utilised data sourced from reputable institutions such as the Association of Molecular Pathology (AMP), Clinical Pharmacogenetics Implementation Consortium (CPIC), Pharmacogenomics Knowledge Base (PharmGKB), and Pharmacogene Variation Consortium (PharmVar) for evidence collection and evaluation. Concerning gene-drug pairs, we filtered the available evidence, focusing exclusively on category A recommendations, and further categorised these pairs by medical specialty. These selected pairs were subsequently phased into clinical services, commencing with deployment at the Heart Centre. Regarding laboratory considerations, we chose the method that aligned best with our laboratory workflow. The aim was to establish a comprehensive database to better explore variant frequencies in our population. 

The final and most challenging part was creating a workflow that seamlessly integrates lab results into the Electronic Health Record (EHR) while simultaneously generating automated clinical guidelines. This requires the creation of a new layer that cross-references genotypes with existing guidelines to produce recommendations, Notably, this component remains in active development. Meanwhile, we initiated the deployment of the pharmacogenomics profiling service with a manual reporting approach.  

An essential determinant of the successful implementation of pharmacogenomics entails rigorous education of healthcare providers. We have devised a multi-faceted approach tailored to address healthcare professionals at varying tiers, ensuring their comprehensive comprehension of pharmacogenomic principles and their proficient utilisation. 

Pushing the frontiers of medical science 

KFSH&RC has established itself as a renowned hub for specialised medical care with a commitment to advancing the comprehension and treatment of rare genetic diseases. 

KFSH&RC's Center of Excellence in Genomic Medicine serves as a testament to the institution's dedication to pushing the frontiers of medical science. Housing state-of-the-art technology and a cadre of distinguished experts, KFSH&RC's advanced genetic services encompass genotyping, expression analysis, bioinformatics, molecular karyotyping, and next-generation sequencing, positioning it as a leader in genomics. 

What sets this centre apart, however, is its resolute commitment to research. In collaboration with the King Abdullah University of Science and Technology (KAUST), KFSH&RC hosts one of the most extensive research programmes on genetic diseases in the region. Ongoing endeavours are directed towards the intricate realm of rare genetic diseases, driven by an unwavering pursuit of identifying novel genes associated with these intricate disorders. The ultimate objective is to promote equity in healthcare for individuals grappling with the challenges posed by rare conditions. 

As a leading provider of tertiary and quaternary healthcare services in the Middle East, KFSH&RC’s mission is to provide the highest level of specialised healthcare in an integrated educational and research setting. 

Dana M. Bakheet, Sateesh Maddirevula and Ahmed Alfares are part of the Clinical Genomics, Centre for Genomic Medicine, KFSH&RC, Riyadh. Bakheet is also part of the Pharmacology Department, College of Medicine, Alfaisal University, Riyadh; Hana Alalshaykh is part of the Clinical and Operational Support Pharmacy, KFSH&RC. 

References available on request. 

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