Genetic influence on medication response

Pharmacogenetic testing can help physicians choose with greater precision the most effective antidepressant for their patients with major depressive disorder (MDD). A study examining the utility of such tests showed that remission, response and relief of depressive symptoms were greater in patients whose care was guided by such tests, compared to patients who received treatment as usual, without genetic accompaniment. “Pharmacogenetic testing will not tell us in advance which antidepressant is most effective for a patient, at least not at the moment. But such tests help us know which medicines may be incorrect, not the best choice or incorrect only for a particular patient”, said researcher John F. Greden, MD, executive director, University of Michigan Comprehensive Depression Center and Rachel Upjohn Professor of Psychiatry, Ann Arbor. Pharmacogenetic testing is not yet routinely used by physicians as a way to improve outcomes for patients with MDD. “There is a lot of skepticism about such tests, there is confusion, people are amazed about this, but there are reasons for this. For example, early studies and publications on pharmacogenetics studied small numbers of genes and variants and had small sample sizes and short follow-up duration. But such tests have come a long way since the early days”, said Greden. "Knowing how to use pharmacogenetic data helps physicians make choices that bring about response and remission", he added.

Researchers have long known that several cancers, other than breast and ovaries, are associated with harmful mutations in BRCA1 and BRCA2, including ovarian cancer, prostate cancer, and pancreatic cancer. A new study, presented at the annual meeting of the American Society for Clinical Oncology in Chicago, describes a treatment approach specific to patients with metastatic pancreatic cancer who had a BRCA1 or BRCA2 mutation.

Chronic pain affects about 20% of the adult population worldwide and is a huge burden on those affected, with a significant negative impact on their quality of life, daily functioning and work productivity. While looking for an explanation of the inter-individual variability in pain perception and drug-induced pain relief, scientists have sought to find the answers in the genes. As of this publication, researchers have identified at least six genes or gene clusters (mostly associated with opioid, adrenergic, and catecholamine pathways) that may be related to pain development. Many physicians already have experience with the great advantage of implementing pharmacogenomics in their daily practice. Dosage adjustments according to a patient's genotype to optimize medicine therapy have been implemented in relevant clinical guidelines and in summaries of product characteristics (SmPC) for particular medicines and medicine classes. Accordingly, translating genomic data is becoming increasingly important in clinical practice in understanding differences in the effect of medications during the treatment of pain.

The European Medicines Agency has initiated an evaluation study of medicines containing fluorouracil and the related medicines capecitabine, tegafur and flucytosine, which are converted into fluorouracil in the body. The evaluation will examine existing screening methods and their value in identifying patients at increased risk for serious side effects.

This month, Karen Daggett celebrated 10 years of life she thought she wouldn't have. On Valentine's Day 2009, she didn't feel well enough to have a dinner with a couple of friends on Marco Island, Florida. But her husband insisted that she go with him and Daggett is grateful for that. “If I had stayed [alone] that night, I probably would have died”, she said. Different genes tell the body how to break down different medicines. A variant in one of those genes can affect how you process one, some, or all of the medicines for which the gene is responsible. Some gene variants can make you so sensitive to a medicine that you only need a dosage half as much as most people to get the same effect. Another variant could mean that you need twice as much. Yet another one could cause you to have a potentially fatal reaction to certain medications.

The number of cancer patients who become seriously ill or even die from the commonly used chemo medication 5-FU can be drastically reduced by testing all patients genetically beforehand and then adjusting the dose if necessary. A Dutch study among 1100 patients in seventeen hospitals now provides definitive proof of this. The main explanation for this has been known for years. 5-FU, which is given by infusion or by pill, is broken down by an enzyme in the liver to an inactive substance. Only 8 percent of all people have a genetic variation that makes that enzyme inactive or less active. The consequence: the medicine is broken down too slowly or not at all, so that the level of active substance in the blood remains high and the medicine has the chance to seriously affect healthy tissues. In this study, the DNA was searched for the four most common variations that reduce or disable the activity of the enzyme involved. In the 85 patients with one of the variations studied, the dose of the cancer medication was adjusted and they received a quarter to half less. The number of patients with serious side effects halved, as described in "The Lancet Oncology". meamedica.com personal medicine tests not only those 4 variations, but also many others, the results of which you can take to your treating doctor.

Migraine is a very common neurological condition with a complex background. Remarkably, there are different reactions to the medicines used for migraines. The ineffective response and degree of side effects are common problems in patients. Several studies show that this condition has an important and complex genetic component related to medicine treatment. Many polymorphisms of genes involved in medication metabolism have been analyzed. These studies show many gene variations, especially on CYP450 (which metabolizes 90% of the medicines) and are the most suitable starting point for both current and future migraine therapy. Pharmacogenetics promise to help find a pharmacological therapy based on the patient's unique genetic characteristics.

DNA analysis is the future of personalized medicine. In Estonia, citizens can already receive free genetic screening and tailored health advice, but what about the protection of that data?
In March of this year, the Estonian government announced that it is spending five million euros to offer 100000 citizens free genetic screening in the remainder of 2018. Since then, the registrations of interested Estonians have been pouring in every week. "We are going to get those hundred thousand before Christmas", says Professor Andres Metspalu on the phone. Metspalu is director of the Estonian Genome Center at the University of Tartu. The genetic material of the Estonians is stored in the biobank of its center. Estonia has an ideal, says the geneticist: "And we call that ideal: precision prevention". On Sunday, VPRO Tegenlicht (a Dutch channel) will delve deeper into this Estonian ideal with the episode "Conquest of our DNA".

The use of pharmacogenomics in the treatment of major depressive disorder (MDD) is supported by study data published in the Journal of Psychiatry Research. Researchers designed an open-label prospective study to examine the efficacy of pharmacogenomics for patients with MDD in both psychiatric and primary care settings. Pharmacogenomic testing was performed for all patients at baseline (N=1871), using genomic DNA isolated from buccal swabs. Medications were classified as congruent or incongruent via genotyping results. Depressive symptoms were assessed at baseline and then at 8 to 12 weeks’ follow-up using the Beck Depression Inventory (BDI).

Finding an effective and tolerable antidepressant for a particular patient can take a long time. During this time, patients are exposed to ineffective medications with potential adverse effects and the harmful effects of the depression itself. The reasons for a negative response to antidepressants can be complex, but genetic components are clearly relevant. The use of pharmacogenetics in antidepressant treatments is therefore intended to improve remission rates of depression and reduce its adverse effects.

Statins are commonly prescribed medicines in the Netherlands. Statins are the first choice for doctors. On average, about 50% of patients stop taking statin medicines. This has several causes. No improvement is felt and/or there are side effects and/or publicity is believed in which the effect is called into question. Often about 25% start again with another statin medicine. Other 25%, however, choose not to use a statin medicine anymore, because of the unpleasant side effects. A study was conducted in Chicago with patients who had stopped taking statin medicines. They had a DNA test and on the basis of this a statin medicine that matched the DNA profile found was prescribed. Almost 60% of this group was ready to continue with the new medication. After 8 months the cholesterol levels were lower. Only 33% of the control group, where the DNA test was not taken, was willing to start using statin medication again.

In 200000 medication prescriptions in 2016, the dose would have been adjusted if pharmacists had been able to request the DNA profile for medicine degradation. According to the KNMP, this is evident from figures from the SFK, presented at the jubilee conference.

Today, the treatment of patients is increasingly looking at unique genetic and biological characteristics. This makes it possible to set up a closely tailored treatment at an individual level. This is called personalized medicine. Pharmacogenetics - part of personalized medicine - makes it possible to determine whether or not a particular medicine is effective in an individual patient or whether it may cause side effects that could lead to hospitalization or even death.

Statins are a cornerstone of the pharmacological treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerosis is a predominant cause of death and morbidity worldwide. Statins are among the most commonly prescribed classes of medicines, and their prescribing indications and target populations have been significantly expanded in the official guidelines recently published by the US and European expert panels. However, adverse effects of statin pharmacotherapy lead to significant costs and morbidity and can lead to non-adherence and discontinuation of therapy. Statin-associated muscle symptoms occur in circa 10% of patients on statins and are the most commonly reported adverse reaction associated with statin pharmacotherapy. Significant clinical and non-clinical research efforts are focused on determining whether genetics can provide meaningful insight into the risk of statin adverse effects in an individual patient. This contemporary review of the relevant clinical research on polymorphisms in several key genes influencing statin pharmacokinetics (eg. transporters and metabolizing enzymes), statin efficacy (eg. medicine targets and pathways) and end-organ toxicity (eg. myopathy pathways) highlights several promising pharmacogenomic candidates. However, SLCO1B1 521C is currently the only clinically relevant pharmacogenetic test with regard to statin toxicity and its relevance is limited to simvastatin myopathy.