PGxCheck...What is our DNA saying?

 

 

 

We need to consider how genetic information

can help us with respect to healthcare. We are able to perform genetic testing more readily,

but how are we using the results? Join in the discussion!

Welcome

Personalized medicine and pharmacogenomics (the influence of genetics on drugs) is here. It is in its infancy and we all will watch it grow. From healthcare professionals to the general public, pharmacogenomics and the broader area of personalized medicine will present a learning curve.


This blog is made possible through an individual making their genetic information available. 

As we learn what this individual's genetics are telling us...and what it is not telling us, we will discuss it. I am sure there will be many questions. We will have individuals from pharmacy, genetics, ethics, law, and other disciplines adding their expertise and thoughts to the discussion. I sincerely hope you will contemplate the information, formulate your thoughts, and participate in the discussion!

What is a drug-gene interaction?

After the post on warfarin, I thought now would be a good time to talk about drug-gene interactions. With warfarin as an example, we can talk about a genetic-dynamic interaction and a genetic-kinetic interaction.




The interaction of a drug and a drug target (a target protein) produced by a variant gene (allele), such as a receptor (click here and click on "drug targets" to review the basics of what a receptor is) results in a genetic-dynamic interaction. In this case the "target protein" for warfarin is the enzyme vitamin K epoxide reductase (sub-unit 1); VKORC1. Warfarin inhibits the activation of vitamin K dependent clotting factors by interacting with VKORC1, resulting in decreased clotting. One of the common uses of warfarin is in patients with the irregular heart rhythm, called atrial fibrillation, where the risk clot formation and stroke is increased. Since this is a case of 'what the drug does to the body', i.e., warfarin inhibits clot formation, this is pharmacodynamics. When someone has a genetic variation resulting in decreased formation of VKORC1, such as the *2 variant, and warfarin is used, there is less target enzyme made and it takes less warfarin to inhibit clot formation. The interaction of warfarin with the product of a VARIANT gene is a drug-gene interaction.


The interaction of warfarin and a decreased or loss-of-function form of the (click here and read about drug metabolizing enzymes drug metabolizing enzyme)CYP2C9 produced by a variant gene (e.g. CYP2C9*2, CYP2C9*3), is a drug-gene interaction. Here, since this is the case of 'what the body does to the drug', i.e., CYP2C9 metabolizes warfarin, this is pharmacokinetic interaction.


So a drug has to interact with a product of a variant gene to be considered a drug-gene interaction. If there is a 'normal' gene producing a 'normal' protein drug target, no interaction would be observed.

Here are some gene forms, tell me if a drug interacts with a given gene (you choose), would there be an interaction?

CYP2D6*4

CYP2C19*1

CYP2C9*11

CYP2C19*3

CYP2D6*41

CYP2D6*1

TPMT*2

Check out http://www.pharmgkb.org/page/cpicGeneDrugPairs. Look up the genes by clicking on the appropriate link under 'publication link'.

What if a person has one 'normal' gene from one parent and one variant gene from the other parent, would there be a drug-gene interaction? Let us know your thoughts!

3 comments | Add a New Comment
1. Diana Ivankovic | October 29, 2013 at 11:20 PM EDT

In the case of TPMT (Thiopurine methyltransferase), the genes exhibits monogenic co-dominant inheritance. There are ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous individuals (1 in 178 to 1 in 3,736) experience severe myelosuppression. Myelosupression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. About half of individuals who are heterozygotes show moderate toxicity, and homozygous wild-type individuals (the majority of the population) show lower active thioguanine nucleolides and less myelosuppression.

2. Katlyn Brown | October 30, 2013 at 10:14 PM EDT

CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI).The wild-type CYP2C19*1 allele is associated with functional CYP2C19-mediated metabolism and could have a gene drug interaction. If a person has one normal gene from one parent and one varient gene from the other there shouldn't be a gene drug interaction because the normal gene would mask the varient gene.

3. DFK | October 31, 2013 at 06:52 AM EDT

Katlyn, good post and while it is certainly reasonable to suspect a normal function gene from one parent would result in normal activity of a given drug target, such as a receptor, transporter or enzyme (again, check out drugsandgenes.com if you have not already), data shows, for some situations that having one variant gene can be significant. For instance, for CYP2C19 when you combine a gene that results in loss-of-function enzyme (*2) with one that result in a gain-of-function (*17), the result is lower than normal drug metabolism and individuals in this case are intermediate metabolizers. THANK YOU FOR YOUR THOUGHTS, it helps lead discussion! What does everyone think about some of the genes listed above?

Add a New Comment

(Enter the numbers shown in the above image)