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!

Metabolizer Phenotypes

In the previous post we discussed different 'metabolizer phenotypes' related to the specific drug metabolizing enzyme CYP2C19. Phenotype means how we 'express' our genetics. Some people express their genetics related to drug metabolism as 'poor metabolizers (PM)', meaning they have 'slow', decreased, or even absent metabolism, these individuals typically require lower doses of active drugs that are metabolized by the given enzyme. If the drug is a prodrug, and requires activation, a higher dose of the prodrug may be required, or another drug can be used. Some people are 'intermediate metabolizers (IM)', meaning that they have decreased metabolism relative to normal metabolism. These individuals typically require a lower dose of an active drug also, but not as low of a dose as a PM would require. Here, a prodrug may not work as well either as less drug would be activated. Some people are ultrarapid metabolizers (UM)', meaning they have increased metabolism relative to normal metabolism. These individuals typically require higher doses than a PM or IM and even a 'normal metabolizer'. These individuals can readily convert a prodrug to its active form. However, most individuals have a 'normal (extensive) metabolizer (EM)' phenotype. This has been called extensive metabolism, but that term can cause some confusion, so think of extensive as 'normal'.


As you will see, there are many different drug metabolizing enzymes. Some of these enzymes metabolize a relatively large percentage of drugs. The family of CYP (cytochrome P450) genes includes CYP2C19, as mentioned before, and CYP2D6, CYP2C9, and many others.

As you have seen, we utilize the star '*' nomenclature (e.g., *1/*2) to identify the two genes each person has (one from each parent) in what we call a genotype or diplotype (two genes). The '*' forms represent different genetics as introduced by a SNP (see post on September 04, 2013 at 7:56 AM EDT) or some other genetic variation. It is important to understand that the '*' nomenclature does not define phenotype the same way for each CYP. So, here is a challenge! The two links below are to current literature (Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines), which defines metabolism phenotype based on the '*' nomenclature. Below are some diplotypes for CYP2C19 and CYP2D6. In you post, define the phenotypes based on the diplotypes, here relating the genetics to metabolism. Note in your post, only provide two examples and leave the others for the next 'poster'. Thanks!

CYP2C19 Genotypes (example diplotypes; click HERE; read the table carefully):

*1/*1

*1/*2

*1/*3

*2/*2

*2/*4

*2/*8

*8/*8

*1/*17

*2/*17

*5/*17


CYP2D6 Genotypes (example diplotypes; click HERE; read the table carefully):

*1/*1xN

*1/*2xN

*1/*1

*2/*2

*1/*2

*1/*41

*1/*4

*2/*5

*10/*10

*4/*10

*5/*41

*4/*4

*5/*5

*4/*5

*4/*6

So, 'have at it' and we will learn something about this '*' nomenclature!

12 comments | Add a New Comment
1. Clayton Miller | October 16, 2013 at 10:48 AM EDT

For the metabolizing drug enzyme of CYP2C19, I looked up the *2/*2 diplotype. I discovered that an individual with this nomenclature is a poor metabolizer, which would indicate deficient activity. The reason for this nomenclature is that the individual would be carrying two loss-of-function alleles. As for the other enzyme, CYP2D6, I looked up the *1/*41 diplotype because it seemed like fun to look up. So, I discovered that this strange combination represents an individual who is an extensive (normal) metabolizer. For this specific case, the individual would have to be either carrying two alleles encoding full or reduced function or one full allele joined with a nonfunctional or reduced-function allele. THAT'S WHAT I LEARNED.

2. Alexandria Lacombe | October 16, 2013 at 11:47 AM EDT

I looked up the *1/*2 and *1/*17 diplotypes for the CYP2C19 enzyme. A person with a *1/*2 diplotype would be an intermediate metabolizer, which means they may not metabolize as fast as someone with a normal metabolism rate. This is due to them having one functional allele and one loss-of-function allele. An individual with a *1/*17 diplotype would be an ultra-rapid metabolizer; they would metabolize at a normal or increased rate. That is because they would have one functional allele and one increased-activity allele.

3. Katlyn Brown | October 16, 2013 at 07:13 PM EDT

I looked up the *1/*1 diplotype for CYP2C19. This form has two functional alleles and a phenotype that is an extensive metabolizer or normal activity. For CYP2D6i looked at diplotype *4/*10 which is an intermediate metabolizer . A person with this genotype carries one reduced and one nonfunctional allele.

4. Allie Harrison | October 17, 2013 at 05:37 PM EDT

I looked up the *1/*3 diplotype for CYP2C19. This is an intermediate metabolizer. An individual would be carrying one functional allele plus one loss-of-function allele. I also looked up *1/*1xN diplotype for CYP2D6. This is an ultrarapid metabolizer. An individual would be carrying more than two copies of functional alleles.

5. Jasmine Hossler | October 20, 2013 at 08:37 PM EDT

I looked up the *5/*17 diplotype for CYP2C19 and found out that this would code for an intermediate metabolizer. This individual would have one loss-of-function allele plus one increased-activity allele. The *1/*1 diplotype for CYP2D6 would indicate a normal metabolizer. This individual would have two fully functional alleles.

6. Celine Raible | October 21, 2013 at 09:08 AM EDT

I looked up the *2/*17 diplotype for CYP2C19. This is an intermediate metabolizer. An individual would carry one loss-of-function allele and one increased-activity allele. For the *1/*2xN diplotype for CYP2D6, this individual would be an ultrarapid metabolizer. An individual would carry more than two copies of functional alleles.

7. Victoria Downey | October 21, 2013 at 10:18 AM EDT

I looked up the *3/*3 diplotype for CYP2C19. This is a poor metabolizer. This individual would carry 2 loss of function alleles.

8. DFK | October 21, 2013 at 10:51 AM EDT

Myranda Smith October 21, 2013 at 948 AM EDT

CYP2C19 *8/*8, Poor metabolizer, 'Higher plasma concentrations of amitriptyline will increase the probability of side effects'. Person carrying two loss-of-function alleles. CYP2D6 *5/*41 Intermediate Metabolizer, able to reduce metabolism of tricyclic, and has the ability to increase probability of side effects. Person carrying one reduced function and one non-functional allele

9. Kim Trask | October 21, 2013 at 03:14 PM EDT

I looked up the CYP2D6 *10/*10 diplotype and found that individuals with theses alleles would be considered extensive metabolizers. These patients would carry either two full or reduced function or one full function allele with a nonfunctional or reduced-function allele. I also found that those with the diplotype *4/*4 for this same gene (CYP2D6) is found to be a poor metabolizer meaning the individual carries no functional alleles and would not be able to properly metabolize the drugs with this gene.

10. Paige | October 22, 2013 at 08:30 PM EDT

I looked up the *4/*5 allele and it is a poor metabolizer and is found in approximately 5-10% of patients. For an individual's genotype, the person is carrying no functional alleles.

11. Meagan Brandt | October 22, 2013 at 09:21 PM EDT

I looked up CYP2D6 *4/*10 and it is an allele of an individual carrying one reduced and one nonfunctioning allele. It is an Intermediate metabolizer and is seen in approximately 2-11% of patients.

12. DFK | October 23, 2013 at 08:34 AM EDT

FYI, Paige's and Meagan's posts were related to CYP2D6.

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