Pharmacogenetic DNA test explained: Part II

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.

... 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.