A study based on data from the Estonian Biobank shows that previously unstudied genetic variants may slow the breakdown of medications, leading to their buildup in the body. The risk of side effects is higher for people who take multiple medications at the same time.
Medications do not affect everyone the same way — some people experience side effects, while for others, treatment may not produce the desired results. A scientific article published in collaboration between researchers at the University of Tartu and physicians from Tartu University Hospital and the North Estonia Medical Center now suggests that the reason may lie in the interaction between medications and genes.
The study is the first to use a clinical trial to describe how previously unstudied genetic variants influence how drugs actually behave in the human body beyond what can be predicted by genetic testing alone.
The research focused on two key liver enzymes — CYP2C19 and CYP2D6 — which are involved in breaking down roughly 40 percent of drugs in clinical use. The scientists identified two missing DNA segments of different lengths in the CYP2C19 gene. They also described how these genetic changes affect the way medications are metabolized in the body. It turned out that people with these gene variants may metabolize drugs significantly more slowly than usual.
According to pharmacogenomics researcher Kristi Krebs, a drug’s concentration in the body typically begins to decline gradually after absorption. However, this is often not the case in people lacking certain DNA segments in the CYP2C19 gene. “We found that in these individuals, the liver enzyme doesn’t function and the drug doesn’t break down at the expected rate — it can instead accumulate in the body. Depending on the type of medication, this can lead to reduced effectiveness or an increased risk of side effects, even at standard doses,” Krebs explained.
Genetic testing not enough
The study also highlighted that genetic testing alone may not always reveal the actual activity of enzymes in a person’s body. The researchers demonstrated that non-genetic factors can also significantly influence how drugs are metabolized. “Our study shows that enzyme activity can be strongly affected by the simultaneous use of different medications, as well as by diseases and lifestyle,” said Kristi Krebs.
The research found that taking enzyme-inhibiting drugs slowed down drug metabolism even in individuals whose genetic profile would otherwise indicate normal metabolic function. This means that even among people with the same genetic background, a drug’s effectiveness and safety can vary greatly depending on what other medications they are taking at the same time. According to the authors, taking such interactions into account allows for more precise prescribing and helps reduce the risk of unexpected side effects.
How drugs behave
The study involved 114 gene donors who carried new or previously little-described genetic variants. Jana Lass, a clinical pharmacist at Tartu University Hospital and a co-author of the study, explained that under medical supervision at either Tartu University Hospital or the North Estonia Medical Center, participants were given small doses of two widely used medications: omeprazole, a drug that reduces stomach acid and was used to assess CYP2C19 activity, and metoprolol, a heart medication used to measure CYP2D6 activity.
“The concentration of both drugs and their metabolic byproducts in the blood was measured at ten different time points, allowing for a precise assessment of the enzymes’ actual activity in the body,” Lass said.
According to Professor Lili Milani, head of the Estonian Biobank and a co-author of the study, the research would not have been possible without the gene donors’ commitment and willingness to contribute to scientific research. “Our goal wasn’t just to describe new genetic variants, but to understand the real impact they have in the human body,” she added.
Goal to arrive at more accurate and safer treatment
According to the researchers, the knowledge gained from the study could help tailor drug dosages more precisely in the future and reduce side effects. “Our hope is that if this knowledge is eventually used in healthcare, people will receive better treatment,” said Lili Milani.
All gene donors can already view their CYP2C19 gene activity in the Minu Geenivaramu portal. Updates to the portal are also underway to ensure the newly identified genetic variants are made available to gene donors in the near future. The researchers emphasize that the study does not mean individuals should change their treatment on their own. “Any decisions about treatment plans must always be made in consultation with a doctor,” Milani noted.
To help integrate testing for new genetic variants into routine medical practice as smoothly as possible, the study’s authors shared their findings early on with providers of pharmacogenetic testing in Estonia.
The study was published in the journal npj Genomic Medicine.
—
Follow ERR News on Facebook and X and never miss an update!