The actor Brenda Fricker once observed that gatherings of older people often resemble an organ recital, the conversations turning quickly into who has what ailment where. More recently the discussions are likely to include who is taking what pills.
A friend mentioned that when he was put on a statin some years ago he developed bad muscle pains – myopathy – so the doctor advised painkillers, which he is still taking with the statin five years later. It is likely he carries one or more genes that predispose him to myopathy if he takes certain statins. Such interactions between genes and medicines have led to the emergence of a new field, pharmacogenomics (PGx), a branch of my own field of molecular genetics.
When I mention PGx to people many tell how they reacted badly to one or other medicine, or how certain medicines did not help them. In some cases reactions to medicines are severe, even life-threatening; these are called adverse drug reactions [ADRs]. Rarely, people who take certain statins can become seriously ill with kidney and heart damage. In a recent letter to The Irish Times (June 7th), Prof Declan Lyons of Limerick University Hospital noted that 16 per cent of all acute hospital admissions in Ireland are related to medication, a pattern seen in other countries.
St James’s Hospital notes 5 per cent of admissions are due to ADRs. Some of these reactions are caused by genes that affect responses to commonly prescribed medicines. International research in PGx in the past 20 years is leading to the conclusion that some drug-gene interactions are so significant that doctors should take them into account when deciding on routine prescriptions. However, few doctors anywhere in the world know much if anything about PGx, with the exception of oncologists and some doctors who deal with situations that are rare in Ireland – for example in treating patients with mutations in the G6PDH gene or patients who are genetically sensitive to some anaesthetics.
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Such clinical uses of PGx are, however, quite specific. The new data on PGx suggest that all doctors need to be aware of the interaction between genes and medicines. It has been mentioned in the first National Genetics and Genomics Strategy report to the HSE (December 2022), with the prospect that PGx will be incorporated into general medicine.
For more than 20 years in the US the government has been sponsoring research on PGx as well as funding the Clinical Pharmacogenetics Implementation Consortium (CPIC). Scientists and doctors in CPIC collate and assess PGx data and advise authoritatively on how they should be used. The Netherlands leads the field in Europe; the Dutch Pharmacy-Pharmacogenomics Working Group (DPWG) collaborates with CPIC and other agencies in updating databases and advice for doctors, pharmacists and patients. Gradually doctors, hospitals, governments and health insurance companies are putting PGx into practice and the NHS is starting a pilot programme.
Current international advice focuses on 50 common variants of 12 genes, where the variation affects responses to about 100 commonly prescribed medicines, including, for example, two well-known statins (simvastatin and atorvastatin), warfarin (blood thinner), esomeprazole (a proton pump inhibitor, ie PPI, which reduces stomach acid), codeine (painkiller) and amitriptyline (antidepressant).
These medicines are actionable, meaning they interact with common genetic variants which can be detected by a quick PCR test on a single saliva sample. New drugs are being added to the list, for example siponimod, approved in 2019-2020 in the USA, Europe and elsewhere, for treating certain cases of multiple sclerosis. Some patients reacted badly, and this was shown by PGx to be related to specific genes. Today MS patients who would react badly can be identified in advance by PGx and unfortunately not be given the drug, while others should be given lower than normal doses. The lists of risk genes and actionable drugs are under continual review.
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The problems due to ineffective or dangerous drug-gene interactions are significant. It has been reported that ADRs cause nearly 200,000 deaths in the EU each year, and some of these are caused by drug-gene interactions. Insurance data in the US show that more than 50 per cent of adults and about 30 per cent of children are taking actionable drugs. Very few are being PGx tested.
Yet the need is there: for example, about 30 per cent of Caucasians have a variant that affects their response to some statins, 25 per cent have a variant affecting the use of some antidepressants and some PPIs, while 30 per cent are at risk from being given the wrong dose of warfarin. More than 90 per cent have at least one risk gene.
David Beggs, founder of Pure Pharmacy, became aware of PGx two years ago and asked me for advice: could PGx be provided in Ireland? After a great deal of work we identified a professional, well-established medical genetics diagnostic service in Frankfurt, headed by Dr Daniela Steinberger, who has pioneered PGx testing in Europe and she agreed to help us.
She was a leader of the EU funded Ubiquitous PGX Consortium (U-PGX) involving doctors and scientists from 18 countries. They developed a set of PCR tests for the 50 variants and trialled them on 7,000 patients in seven hospital laboratories in different countries. The final report of U-PGX in The Lancet in February 2023 led to the conclusion PGx testing before prescribing “led to 30 per cent fewer serious side effects”.
I decided to get a PGx test from Frankfurt. The PCR analysis shows I carry five risk genetic variants that interact with 27 commonly-used drugs. Fortunately, I am not taking any of them, but I carry the electronic laboratory report on my phone which contains clinical advice on the use of these drugs that I can show to physicians and pharmacists. I used the list recently at a medical consultation where my sensitivity to codeine might have been an issue.
A PGx test starts with a simple saliva sample that will be coded for confidentiality and sent to an authorised laboratory. The results and reports from Frankfurt can be downloaded from the web by the client and shared with their doctor and/or pharmacist. The reports are advisory and need to be interpreted for the client and then acted on, or not as the case may be, before being placed on confidential medical records and of course kept on personal phones and computers.
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In due course everyone will take a PGx test. The data will be a part of everyone’s computerised medical record to be consulted automatically when a prescription is given. Doctors will be alerted if a new prescription presents a drug-gene risk, so there will be fewer adverse reactions and treatments will be genetically optimised in drug selection and dose.
With fewer side effects and better responses to treatments, patients will be more inclined to take their prescriptions as directed. There will be fewer repeat visits to surgeries or hospitals. Patients will be healthier with greater confidence in their drugs. Insurance companies and the national health service will decide to pay for PGx. The main guide to what should be done is common sense. PGx will lead to better health and reduce the cost. The Mayo Clinic is developing a PGx programme – “The right drug for the right patient at the right dose”.
Regrettably the HSE is unlikely to put a PGx service in place for some years, given the many challenges. The private sector is likely to lead the way. Hospitals will benefit if they set up a PGx service, co-ordinating with the health insurance companies, GPs and pharmacists. They may well focus on people who are at higher risk, notably those who are taking several drugs – polypharma, which is associated with age.
One person in five over 50 is taking more than five drugs; the risk of ADR increases from 13 per cent taking two drugs, to 58 per cent taking five, to 82 per cent taking seven or more. David Beggs estimates from his own practice that last year there were 17.5 million actionable drug prescriptions in Ireland; the total number of all prescriptions is increasing rapidly, and by 40 per cent in the US since 2004. As drugs become an even more important and expensive part of our lives, we should do all we can to make sure we are taking drugs that suit our genes – personally.
David McConnell is a fellow emeritus at Smurfit Institute of Genetics, Trinity College Dublin. He is an adviser to GeneCheck a service of Pure Pharmacy
