Pharmacogenetic DNA test explained: Part II


Pharmacogenetic DNA test explained: Part II

In the previous blog on the subject of pharmacogenetics we explained how drugs are processed in the body and why there are lots of individual differences (see: Pharmacogenetic DNA test explained). A pharmacogenetic DNA analysis makes it possible to identify, as a targeted, preventive measure, which drug and dose are best suited to a particular individual. In this way serious side effects can be avoided and drugs can be used more effectively. 

But exactly what information do you receive in such a pharmacological profile and what do these results mean? In this blog we pick up where we left off and look at this subject in greater depth. 

DNA variations and their impact on enzyme activity

In the previous blog we explained how DNA variations can lead to significant individual differences in sensitivity to drugs. Such variations are not uncommon; almost everyone has one or more DNA variations that could be responsible for an abnormal response to the standard dose of commonly used drugs. 

The enzyme CYP2D6 is involved in the processing (metabolisation) of around 20 to 25% of all drugs and is therefore one of the most important liver enzymes. A wide range of drugs are processed by this enzyme, including antidepressants, antipsychotics, beta blockers and opioids. 

Many different DNA variants have been described that have an impact on the activity of the enzyme CYP2D6. Some of these are relatively common, while others are rare. Most of them result in reduced or significantly reduced enzyme activity, but there are also variations that can accelerate the activity of the enzyme.

Besides genetic variations, age, lifestyle, eating habits and the use of drugs also influence how the enzyme CYP2D6 functions.


From genotype (DNA variants)… 

To obtain a pharmacogenetic profile, DNA variations are identified in genes of important (liver) enzymes, transport proteins and receptors. In many cases two copies of the DNA are present: one copy from the father and one copy from the mother. If two copies are present without any mutation, activity will be normal.

When a genotype is determined mutations are indicated by so-called alleles. Each allele has a name consisting of an asterisk and a number. An example of a CYP2D6 genotype is CYP2D6*1/*4. As everyone has two versions of a gene (one originating from your father and the other from your mother) a genotype shows the result for both alleles.

In Europeans, for example, the CYP2D6 variants *4, *10 and *41 are common. If no variants are found in a gene, this is indicated by the *1 allele. If the genotype is CYP2D6 *1/*1, this means that no variants have been found in either version of the gene.

... to phenotype (difference in metabolism)

The combination of the two alleles identified can then be translated into an impact on metabolic activity (phenotype). Each allele can have a different impact on the metabolic activity of the enzyme. 

The *10, *17 and *41 alleles of CYP2D6, for example, have lower activity than the *1 allele. These variants lead to reduced metabolism (IM = intermediate metaboliser). A *4 allele is even completely inactive: this is referred to as a ‘poor metaboliser’ (PM). A normal (non-anomalous) metabolism is referred to as an EM (extensive metaboliser). Lastly, it is also possible to have a significantly accelerated metabolism: UM (ultrarapid metaboliser).

Each gene therefore has its own DNA variants and unique alleles that can be translated into metabolic activity. A *4 allele of CYP2D6 therefore says nothing about the activity of a *4 allele of CYP2C19. In addition, more variants have been described for some genes than for others. At iGene we take the most recent information and recommendations from the KNMP (Royal Dutch Association for the Advancement of Pharmacy) and DPWG (Royal Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group) as a basis.

PM = poor metaboliser; significantly reduced or absent metabolic activity

IM = intermediate metaboliser; reduced metabolic activity
EM = extensive metaboliser; normal/average metabolic activity
UM = ultrarapid metaboliser; accelerated metabolic activity


... and adapted dosage of drugs

Let’s assume that the analysis of your DNA reveals that you have a slow-acting CYP2D6 enzyme. In the pharmacogenetic overview you will then see, for example: CYP2D6 *4/*11: slow acting or PM (poor metaboliser). How can a doctor or pharmacist use this information when prescribing drugs?

A slow-acting enzyme can have various effects on dosage, depending on the type of drug in question. In the case of inactive drugs, so-called prodrugs, an activation step has to take place first within the body to create a biologically active substance. If you have a reduced metabolism, this can lead to a delay in the availability of this active substance and possibly to reduced efficacy of the drug. Other drugs do not require such an activation step; in this case a reduced metabolism can result in the active substance being broken down more slowly and remaining available for a longer period of time, increasing the risk of side effects. If you have a faster-acting enzyme, the dosage also depends on the type of drug. 

On the basis of the enzyme activity identified, a doctor or pharmacist may decide to adapt the standard dose or opt for a different drug. On no account should you adjust the dose yourself! It is also important to be aware that it is not only genetic variations that influence the activity of an enzyme. Other factors, such as age, lifestyle, eating habits and the use of drugs, also have an impact.


Presentation of the results

Als de DNA-analyse is afgerond, worden de resultaten op twee manieren gepresenteerd: het farmaco-profiel en een medicijnoverzicht. 


In het iGene farmaco-profiel worden bijna 20 belangrijke enzymen, transporteiwitten en receptoren in kaart gebracht. Per item wordt weergegeven welke allelen bij jouw zijn gevonden, welk effect dit heeft op het metabolisme, welke varianten in zijn getest en welke medicijnen gerelateerd zijn. 

Deze informatie kun je eenvoudig delen met de huisarts of apotheker.


In deze lijst zie je in één oogopslag op welke medicijnen je mogelijk (over)gevoelig reageert bij een standaarddosering. Er zijn 48 geneesmiddelen in opgenomen waarvoor een actief dosis-beleid wordt geadviseerd, gebaseerd op informatie van het DPWG en CPIC. 

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