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!

Chest Pain, Coronary Artery Blockage and My Antiplatelet Therapy!

One of the aims of personalized medicine is to optimize drug therapy. This is a result of providing the patient with the right medication, which is going to work for them (efficacy), while avoiding adverse effects (adverse drug reactions). Avoiding adverse drug reactions will make the patient adhere to taking their medication. This is a "win-win-win" situation.


Here are my results relative to the drug metabolizing enzyme CYP2C19 and the drug clopidogrel (you may have seen commercials for the brand name Plavix) and these results would be very important if I were to requires an antiplatelet drug to keep my blood from forming dangerous clots that could result in a second heart attack and death...I will explain.

Let's say I suffer a heart attack and it is noted that one or more of the arteries that supply my heart tissue (muscle) are blocked with plaque. This can result in another clot and cause another heart attack, or death. It is somewhat common in this situation to have a stent (tube) placed in the arteries to keep blood flowing. This puts me at risk for a clot to form at the site of the stent and another heart attack. It is standard to give people with a stent at least two antiplatelet drugs. Typically aspirin and another drug. This can help prevent clot formation. One of the best selling drugs for this purpose is clopidogrel (Plavix). Clopidogrel is a prodrug, meaning it needs to be activated by the body to work. The gene that produces the metabolizing enzyme, a drug target protein, that 'activates' clopidogrel is CYP2C19. Notice the gene is italicized whereas earlier, the enzyme of the same name was NOT italicized. This is by convention and I thought I would just 'throw this information in'.

The issue is...that my genetics will dictate whether clopidogrel will work for me. Some people have a CYP2C19 gene that produces an inactive (loss-of-function) enzyme. Remember that we get a gene from each parent, so an individual can have two 'normal' genes, one 'normal' and one 'loss of function' gene or two 'loss-of-function' genes. There are other forms too, like a 'gain-of-function', but we will not discuss this further. We have a way of defining these potentials:

*1/*1 = normal/normal = normal (extensive) metabolizer
*1/*2 (and other *s, e.g., *3) = normal/loss-of-function = intermediate metabolizer
*2/*2 = loss-of-function/loss-of-function = poor metabolizer

Data shows that intermediate metabolizers and poor metabolizers should receive a drug other than clopidogrel.

So, the question is what am I? Well, here is the data:
CYP2C19 result_1

CYP2C19_2

Notice a couple of things. First, the rs#. I think I mentioned this earlier, but if not... the rs# is a specific and unique identifier of a given SNP as found in the National Center for Biotechnology Information database called 'dbSNP'. So rs4244285 refers to the above SNP in the specific position on the CYP2C19 gene where A replaced G. G is the 'normal', most common base found at that position, so one parent passed along the A instead of a G. That single nucleotide change (polymorphism) resulted in me not being able to convert as much of the clopidogrel prodrug to its active form, meaning that I would be at increased risk of another clot, heart attack and death if I were using clopidogrel as a second antiplatelet medication. I have since confirmed my *1/*2 status by testing done in my lab.

From the personalized medicine standpoint, this testing allows for me to receive a drug that is efficacious (that will work for me; like prasugrel or ticagralor, i.e., something other than clopidogrel), will avoid an adverse event...hopefully, here avoiding a clot and death! Also, I will be adherent to the medication because it can be a matter of life or death!

So, time to look at some data and answer some questions. Click HERE to look at some data from the Clinical Pharmacogenetic Implementation Consortium (CPIC) and find the table that shows the frequency of the *2 form in various populations. Let's see which populations have the highest frequency of the loss-of-function *2 allele (gene form). Go ahead and put this in your comment. Also, think about what this may mean for a given individual from a specific population.

African

American

East Asian

European

Middle Eastern

Oceanian

South/Central Asia

This is helpful in considering who may be more likely to have a loss-of-function gene form (allele) when there is no individual genetic data. Who has what frequency? Who would you be most likely to give an antiplatelet drug, other than clopidogrel, to? Of course, we REALLY need the individuals genetic data! By the way, the reason we can do all this is that technology has advanced to allow us to look at DNA more efficiently! DNA testing is more available and affordable.


6 comments | Add a New Comment
1. Kara Horvath | October 14, 2013 at 02:55 PM EDT

To my understanding, the chart shows that the Oceanian population has the highest frequency for the *2 (loss-of-function allele). This means that most Oceanians would not be able to take clopidogrel as the second antiplatelet drug.The Middle Eastern and American populations have the least chance of having this allele, so most of these people would be able to take clopidogrel to prevent blood clots. However, I find it interesting that you have the *1/*2 allele. How is the intermediate metabolizer represented on this chart? And what does the *3 indicate? That seems to make up the majority of the \left-overs\ of each population.

2. Katlyn Brown | October 15, 2013 at 03:46 PM EDT

Oceanian populations have the highest frequency at 0.61 for the *2 allele meaning that they could not take clopidogrel. The next highest would be South/Central Asian with 0.35. Where would the cut off be for people who could not take this medication ?

3. DFK | October 15, 2013 at 04:11 PM EDT

Kara stated 'I find it interesting that you have the *1/*2 allele. How is the intermediate metabolizer represented on this chart? And what does the *3 indicate?' Response: The chart is showing individual alleles. Remember that you receive one gene from on parent and a second from your other parent. They may be the same form, or different. I received one 'normal' gene (*1) and one variant allele (*2). So I have a *1/*2 'diplotype' (combination of two genes using the '*' terminology). The *3 is another form of the gene (allele) that is also a loss-of-function form. Data shows, that related to the use of clopidogrel, individuals with one or two loss-of-function form(s) (allele(s)) are at risk of adverse events, like clots, heart attacks, and death and should receive antiplatelet drug other than clopidogrel.

4. DFK | October 15, 2013 at 04:17 PM EDT

Katlyn asked 'Where would the cut off be for people who could not take this medication?' Response: (Taken from the response to Kara) Data shows, that related to the use of clopidogrel, individuals with one or two loss-of-function form(s) (allele(s)) are at risk of adverse events, like clots, heart attacks, and death and should receive antiplatelet drug other than clopidogrel. So any combination of the 'normal' gene and a 'loss-of-function' gene (e.g., *1/*2, *1/*3) or combination of two 'loss-of-function' genes (e.g., *2/*2, *3/*3, *2/*3) would mean an individual would likely not benefit optimally from clopidogrel use...AND... the combination of a 'gain-of-function' form (*17) and a 'loss-of-function' form also results in increased risk of adverse events, thus another antiplatelet drug (other than clopidogrel) should be considered.

5. Joshua Macks | October 17, 2013 at 07:27 PM EDT

Oceanian populations have the highest frequency of the *2 allele. My question is, what is the reason for taking a drug that requies an enzyme to catalyze a reaction when there are other drugs that do not require to be catalyzed? Is there a certain advantage to that drug?

6. Kortney Manning | October 19, 2013 at 06:43 PM EDT

Oceanian has the highest frequency of *2, followed by South/Central Asian, East Asian, European and African are tied at 0.15, and Middle Eastern and American are tied with the lowest frequency of 0.12. Since this test only shows how well Clopidogrel works in your body, would that automatically mean that one of the other drugs would work better, or could they even possibly be worse with your genetics than Clopidogrel?

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