EnvisioningHealth - Changing Lives One Idea at a Time | Innovation X Healing
A Singaporean pilot study on pharmacogenomics sharpens the focus of precision medicine, tailoring treatment efficacy for the region's diverse genetic landscape.
Issue 3 | December 2023
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Have you ever wondered why certain medications appear less effective for you than others? Or why a common drug could pose life-threatening risks to certain people?
The effect of drugs on different people is the focus of pharmacogenomic (PGx) testing, which seeks to decode the genetic factors within our DNA. PGx - an example of precision medicine - will be a crucial tool to deliver the right treatment to the right people at the right time.
In that respect, Singapore's pursuit of precision medicine is driven by Precision Health Research, Singapore (Precise). Established in 2021, Precise is coordinating a decade-long, whole-of-government initiative to realise Singapore's National Precision Medicine strategy. The project, which involves the National University Hospital's (NUH) Dr Elaine Lo and Professor Goh Boon Cher as the lead pharmacist and the principal investigator respectively, aims to generate and collate data of up to one million residents, integrating genomic, lifestyle, health, social and environmental data.
Now in its second phase, the initiative involves a PGx pilot study that assesses the genetic factors affecting individual responses to 30 drugs, including codeine for pain management, cholesterol-lowering statins, several chemotherapy drugs such as mercaptopurine and antidepressants like amitriptyline.
Sifting through millions of differences in an individual's genetic blueprint to pinpoint the origins of disease is akin to scouring for a needle in a haystack. Compounding that challenge is the search for the optimal medication to combat a specific disease. PGx acts like a 'metal detector' - identifying DNA variations that can predict how a person will react to certain drugs.
"For instance, the presence of one genetic variant may indicate that the corresponding protein cannot effectively metabolise a given drug, potentially leading to a build-up of the medication in the body and increases the risk of side effects," explains Dr Elaine Lo, who is a principal clinical pharmacist at NUH. "On the contrary, the presence of another variant may cause a drug to break down more rapidly than intended, which diminishes its therapeutic effect."
The drugs selected in the PGx pilot come with a story of its own. Take mercaptopurine, an oral chemotherapy drug prescribed for childhood leukaemia, which has caused severe complications like infections, anaemia and bleeding in some patients. Studies by researchers from the St Jude Children's Hospital in the United States attributed these reactions to a gene variant known as Thiopurine Methyltransferase, or TPMT.
In Singapore, similar adverse effects were observed in children not carrying the TPMT variant, confounding researchers for many years. The puzzle was solved when a collaborative research effort between St Jude and a team of Singaporean paediatric oncologists, including Professor Allen Yeoh, Head & Senior Consultant, Division of Paediatric Haematology and Oncology, Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, NUH. They discovered a different gene called Nudix Hydrolase 15, or NUDT15, in some of the local children. This gene, affecting the metabolism of mercaptopurine, is notably prevalent in Asian populations, underscoring the importance of localised research when it comes to precision medicine.
The analysis of large-scale genomic databases is a critical enabler of precision medicine across Asia, where 60% of the world's population resides. Despite this demographic significance, Asian genetic lineages remain under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant to these populations.
The PGx pilot, tapping into a targeted 1,000 adult volunteers from institutions like NUH, administers a genetic screening to identify variants that may affect the medication efficacy for common ailments such as stroke, cancer and depression. The initiative also includes establishing a hotline that doctors can dial to contact a team of trained pharmacists who can provide PGx-guided drug information support. Being implemented is an alert system to warn prescribers of drug-gene interactions.
"Pharmacogenetic guidelines on drug-gene pairs exist elsewhere, but Singapore must construct its own, as the research in Western populations is not always applicable to Asian populations," says Professor Goh Boon Cher, who is a senior consultant at the Department of Haematology-Oncology, National University Cancer Institute, Singapore.
"We are working towards building a local team of experts who can curate the data and make sure that it pertains to our population of predominantly Chinese, Malays and Indians, and other races," adds Prof Goh.
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