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!

If I had atrial fibrillation and needed warfarin...

Here is the description of atrial fibrillation from the National Heart Lung and Blood Institute (NHLBI):


Atrial fibrillation (A-tre-al fi-bri-LA-shun), or AF, is the most common type of arrhythmia (ah-RITH-me-ah). An arrhythmia is a problem with the rate or rhythm of the heartbeat. During an arrhythmia, the heart can beat too fast, too slow, or with an irregular rhythm.


AF occurs if rapid, disorganized electrical signals cause the heart's two upper chambers—called the atria (AY-tree-uh)—to fibrillate. The term "fibrillate" means to contract very fast and irregularly.


In AF, blood pools in the atria. It isn't pumped completely into the heart's two lower chambers, called the ventricles (VEN-trih-kuls). As a result, the heart's upper and lower chambers don't work together as they should.


People who have AF may not feel symptoms. However, even when AF isn't noticed, it can increase the risk of stroke. In some people, AF can cause chest pain or heart failure, especially if the heart rhythm is very rapid.


AF may happen rarely or every now and then, or it may become an ongoing or long-term heart problem that lasts for years.


One of the goals of treating AF is to:

  • Prevent blood clots from forming, thus lowering the risk of stroke.

People who have AF are at increased risk for stroke. This is because blood can pool in the heart's upper chambers (the atria), causing a blood clot to form. If the clot breaks off and travels to the brain, it can cause a stroke.

Preventing blood clots from forming is probably the most important part of treating AF. The benefits of this type of treatment have been proven in multiple studies.


Doctors prescribe blood-thinning medicines to prevent blood clots. These medicines include warfarin (Coumadin®), dabigatran, heparin, and aspirin.


People taking warfarin (and some other) medicines need regular blood tests to check how well the medicines are working.


OK that is the information, adopted from the NHLBI. Now for some pharmacogenomic information. By the way, the strict definition of pharmacogenetics is the relationship between a single gene and drug response, whereas, pharmacogenomics is the relationship between all genes (the genome) and drug response...a slight difference. I use pharmacogenomics here, because there are, at least, two genes involved in an individual's response to warfarin. Here is my information:


23andMe 1



23andMe 2


So, how does this information impact the dosing of warfarin for me? Here is a dosing table for initial dosing of warfarin based on genetics. Please consider the following:


CYP2C9


I know this is a "big chart" from the supplementary material provided by the Clinical Pharmacogenetic Implementation Consortium (CPIC), published in Clinical Pharmacology and Therapeutics in October of 2011 (free access article), however, you should be able to put together my genotype (*/*) and comment on my metabolizing of warfarin by the CYP2C9 metabolizing enzyme, based on my CYP2C9 genotype.


Then there is the issue of the drug (warfarin) target, here, an enzyme called VKORC1. Here is some information from the same CPIC source:


Individuals which have an A instead of a G at rs9923231 have increased sensitivity to warfarin. Here, there is less target protein made for warfarin to affect, so you need less warfarin...or in other words, there is warfarin sensitivity. So, look again at the above information and tell me what dose of warfarin you think I should start on, based solely on my genetics. I challenge you to look up warfarin and see what some of the adverse, or side effects there are and discuss what may happen to me if I get the wrong dose of warfarin. I look forward to some thoughts on this!

6 comments | Add a New Comment
1. Diana Ivankovic | October 23, 2013 at 11:34 PM EDT

One of the main side effect of a warfarin overdose is bleeding. This can include obvious bleeding (nosebleeds, fresh blood in stool orvomiting of blood) or bleeding that is less obvious (such as internal bleeding). An overdose can occur in various ways. Besides an intentional overdose, an overdose with warfarin can occur as a result of certain food or drug interactions.

The antidote for a warfarin overdose is vitamin K, which can be given in tablet or injectable form. These treatments must be done carefully. If too much vitamin K is given, this can reverse the effect of warfarin so much that it is no longer effective for preventing blood clots. If too little is given, the risk of bleeding will persist. In your case, the dose can stay lower, since you are sensitive to warfarin.

2. Kara Horvath | October 25, 2013 at 09:02 AM EDT

For the SNP rs1799853, you have a genotype of CC, and for the SNP rs1057910, you have a genotype of CC. When AC at rs1057910 as shown in the CPIC chart, an individual has decreased enzyme activity. So, you are at risk of metabolizing this drug more slowly. If you take too much of this drug, the enzyme won't be able to metabolize warfarin fast enough, so you could experience adverse drug effects, such as with Vitamin K. However, you say that at rs9923231, individuals having A instead of G have increased sensitivity, and your information shows a genotype of TT for that SNP. What does TT mean for that?

3. DFK | October 25, 2013 at 12:42 PM EDT

Kara, GREAT question! When we think about the double-strand DNA, there are 'complimentary' bases on each strand...G is always paired with C and T is always paired with A. So, for rs9923231, where there is usually a C on one strand and a G on the corresponding strand for both genes (one from each parent), I have a T on one strand and a corresponding A on the other strand on both genes. You may see this reported as TT as 23andMe has done. At least, this is one potential explanation. There have been numerous names for this.

4. DFK | October 25, 2013 at 12:51 PM EDT

Please note for the 'CPIC' table above (big table), there are many examples of SNPs. When you see the conventional designation, such as: C (greater than sign) T at rs1799853 (*2; the first example), this mean T replaced C. Where you see: A (greater than sign) C at rs1057910 (*3; the second example), this means C replaced A...and so on.

5. Kara Horvath | October 25, 2013 at 03:03 PM EDT

So, since we also have to consider the complimentary bases in your genotype and A and T are base pairs, the rs9923231 SNP with genotype TT would indicate that you have an increased risk of sensativity to warfarin, which parallels what the other SNPs are showing.

6. Paige Ordean | November 11, 2013 at 05:16 PM EST

Bleeding is the most common side effect while using Warfarin, but some of the other adverse effects are anaphylaxis, hypersensitivity, and cholesterol microemboli, which can lead to skin necrosis, death, or \purple toe\ syndrome. Other signs of cholesterol microemboli include rash and intense pain in the lower extremities. Since there is an increased risk of sensitivity to warfarin, you should definitely stay on a low dosage and be on the lookout for any abnormal symptoms.

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