Genes influence how each person responds to a drug

Disease and treatment 4. aug 2021 3 min Associate professor, Research Pharmacist Christiane Gasse Written by Kristian Sjøgren

Genetic variants strongly influence how rapidly individuals metabolise drugs. A researcher says that personalised drug dosing needs to be in focus.

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Individuals differ greatly in how rapidly they break down medicine in the body.

Some people have genetic variants that enable them to metabolise drugs rapidly, and others have genetic variants that make drugs stay longer.

However, current practice is to treat everyone with the same dose without considering genetic differences. Some people will not get the effectiveness they need from medicine. Others may get such a strong effect from the medicine that it approaches overdose with side-effects.

Now a new study in Denmark shows that many people have several genetic variants that predispose them to reduce or increase the effectiveness of drugs, including psychotropic drugs such as antidepressants.

The study also shows that people with a mental disorder do not differ from a broad cross-section of the population in the presence of several genetic variants.

“We have long known that people may differ in how quickly they metabolise drugs. However, this information is very often not integrated into clinical practice. One reason is that we have not yet found any good methods to assess the effect of not just one genetic variant but several. In this study, we elucidated some of the bioinformatic potential of analysing the genetic predisposition to metabolise drugs more rapidly or slowly and thereby implement personalised drug dosing,” explains a researcher behind the new study, Christiane Gasse, Associate Professor and Research Pharmacist, Department of Clinical Medicine, Aarhus University.

The research has been published in Translational Psychiatry.

Dosing is based on the average, but we all differ

Christiane Gasse and colleagues studied how the general population metabolises psychotropic drugs and others.

Research has shown for many years that various genetic variants can result in people metabolising drugs more rapidly or slowly.

People who metabolise medicine faster may need a higher dose to get the desired effect.

Conversely, people who clear the drug from the blood slowly may need a lower dose to avoid overdose or side-effects.

Although researchers have studied the relationship between how people with individual genetic variants metabolise drugs for many years, Christiane Gasse thinks that there has not been enough focus on the overall prevalence and how this can be translated into clinical practice.

She and her colleagues are currently investigating this.

More than 80,000 people studied

The researchers obtained genetic information on 42 genetic variants related to the absorption or effect of clinically relevant and recommended doses of drugs. The genetic information came from a large population-based sample from the Integrative Psychiatric Research consortium iPSYCH2012 case-cohort that contains data on 51,464 individuals with a severe mental disorder and 26,220 individuals randomly selected from the population. The data for individuals with mental disorders and individuals randomly selected from the population were retrieved from the Danish Neonatal Screening Biobank within the Danish National Biobank at Statens Serum Institut linked to health data from other medical registries in Denmark.

The participants had their genomes mapped via genetic markers, and the researchers then trawled through the genomes searching for genetic variants that were previously associated with metabolising drugs more rapidly or slowly.

“The purpose was to perform a large population study of how these genetic variants are distributed in the population and whether people with a mental disorder differ from people without a mental disorder,” says Christiane Gasse.

87% have several genetic variants associated with drug response or metabolism

The results revealed two things.

· The people with a mental disorder did not differ from the general population sample in genetic variants. Both groups had the same prevalence of the examined genetic variants associated with drug response or metabolism. Christiane Gasse explains that one could have speculated about a difference based on selection for genes or factors associated with the risk of mental disorders, but this appears not to be the case.

· The study shows that 87% of the population have a relatively large number of genetic variants associated with drug response or metabolism. Thus, 87% of the participants have three or more of these genetic variants, and 40% have more than five of these.

Christiane Gasse elaborates that the result is useful because it can provide long-term insight into how various genetic variants interact to produce an overall treatment effect.

“We can get a much better idea of this when we determine the differences in genetic variation between people,” she explains.

Mathematical model calculates drug dosage

Christiane Gasse says that the study does not conclude this research. On the contrary, the study is the starting-point for several studies in which the researchers will examine in greater depth how genetic variants are expressed.

“This study showed that people differ in genetic variants that strongly affect how rapidly they metabolise drugs. The next step is to determine how a genetic variant is associated with treatment outcomes among individuals,” says Christiane Gasse.

Christiane Gasse elaborates that the study has now provided the researchers more information they can enter into mathematical models that will help to calculate the right dose for each individual in the future.

“We lack this. We need to be able to calculate the right dose for each individual based on not just their genetic profile but also on what other medication they are taking. We are following this precision medicine approach with this study,” concludes Christiane Gasse.

Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case–cohort sample” has been published in Translational Psychiatry. In 2017, the Novo Nordisk Foundation awarded a grant to Christiane Gasse for the project Pharmacogenetic Testing: Who and Why? Pharmacoepidemiological Descriptive and Analytical Studies of Pharmacogenomics of Treatment Response in Psychiatry and in the General Population.

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