Published 2.11.2023
Text: Johanna Kiiski
Picture: Shutterstock
Editing: Viestintätoimisto Jokiranta Oy

 

There is great individual variation in how we respond to drugs. A number of biochemical reactions are required for a drug to be absorbed in the body and distributed to the target tissue, to take effect or turn into active substances, and finally, to be eliminated from the body. Biochemical reactions also determine the duration and intensity of medication. These reactions are influenced by age and gender, other medications, possible diseases and hormonal factors, such as pregnancy. The individual’s genes play a particularly significant role. Research has shown that practically every person carries at least one, but often several gene variants that influence the activities of pharmaceuticals.

Hundreds of genes of pharmacogenetic relevance have already been identified. In most cases, they encode liver enzymes or transporter proteins that are responsible for the metabolism of drugs in the human body. Variation in these genes may result in changes in the efficacy and action of drugs. For example, approximately one third of patients suffering from depression gain no help of medication, and unpleasant adverse effects are experienced by many. This is often due to individual genetic variation. Correspondingly, following a heart attack or stroke, people are frequently prescribed statins as medication to reduce the risk of a new event. The effect of statins, however, will remain deficient if the individual has certain variants in specific liver enzymes. In these cases, the risk of a new event will not be reduced as expected.

Within healthcare, gene testing is available for many different pharmaceutical therapies. On the basis of the test results, it is possible either to adjust the dosage or select an alternative drug.

Pharmacogenetic testing will advance the safety of medicinal treatments and decrease the adverse effects and mortality caused by medication. Testing also has a positive impact on environmental loading, since drugs that remain unused due to their side effects will not end up being disposed of as household waste or entering our waterways through wastewater. The downsides of pharmaceuticals are also a considerable financial burden to healthcare. As the results of individual gene tests are permanent, they can be relied on whenever new medications are needed throughout a person’s lifetime.

 

Finns have a distinctive genome

Philosopher Pythagoras found already in Ancient times that, in some individuals, eating fava beans resulted in severe haemolytic anaemia, in which red blood cells break down at an accelerated rate. Pythagoras believed this happened because the fava beans contained dead people’s souls. Today, we know that the condition is caused by mutations in the glucose-6-phosphate dehydrogenase (G6PD) enzyme located in the X chromosome. These mutations result in the deficiency of the G6PD enzyme, which protects the red cells from breakdown.

Foodstuffs, such as fava beans, or pharmaceuticals, including malaria drugs, antibiotics and pain killers, may trigger a serious disease known as favism in those who bear this particular gene mutation. In Finland, these enzyme variants are rare but severe G6PD deficiency occurs commonly in, for example, certain Mediterranean, Middle East and Asian countries.

Finns have a distinct native genome, so there are features in our gene pool that are not generally seen in other countries. This variation may have an influence on the metabolism of different drugs. Tailored gene tests are thus needed in Finland to facilitate the mapping of pharmacogenetic changes specific to Finns. Globally, our native genome is a highly valued research subject.

As an example, the number of people who are ultra-rapid metabolizers of the CYP2D6 enzyme is higher in Finland than in other Nordic countries. For these individuals, the response to many antidepressants may remain deficient as the drug is too quickly eliminated from the body, or the dosage of a pain killer may rise too high as the medicinal agent turns into active substances too rapidly. Codeine, for example, is a so-called prodrug that is metabolized to morphine by the CYP2D6 enzyme.

 

Towards more individualized medication

Pharmacogenetics is the study of the impact of individual genetic differences on drug response. Inherited variability has a strong and permanent impact on individual response on medication, and dosing recommendations based on genotypes are already available for many drugs. Despite advancements in the field, most of the pharmacogenetic variation is still unknown, so more research is needed, especially in different populations and communities. The elderly, people with multiple diseases as well as children are at a high risk of adverse drug reactions, and research-based knowledge would benefit these groups, in particular.

Our research is aimed at identifying new variations affecting drug response, with particular focus on the mutations of the DPYD gene in the Finnish population. This specific gene encodes an enzyme that regulates the metabolism of fluoropyrimidine drugs that are used in the treatment of many of the most common cancers. The inactivity of the enzyme may result in severe adverse events, even death, in people treated with fluoropyrimidines. Therefore, it is important to check the enzyme function by means of gene tests prior to starting the medication. We are looking for mutations that have not been identified previously in the Finnish population – with the ultimate target of providing more individualized and safer medicinal treatment.

More information (in Finnish and Swedish) about the genetic variation affecting drug response is available online at (in Finnish): https://www.terveyskyla.fi/laaketalo/perimä-ja-lääkkeet

 

 

 

 

 

 

PhD Johanna Kiiski earned her doctoral degree from the University of Helsinki in 2018 with a thesis concerning the identification of new gene variants in the Finnish population predisposing to hereditary breast cancer. Currently, Kiiski serves as a geneticist and post-doctoral researcher in the Department of Clinical Pharmacology at the University of Helsinki and HUS.