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 JES did was send in a saliva sample that provided information that he could use in the future. This is preemptive genetic data. It is essentially in a database that he can query when there is a need to look at the information. The raw data provided by the direct-to-consumer company included over 960,000 SNPs!
This is where electronic health records and other information technologies will need to be used in healthcare. Legislation is in place to direct hospitals and physicians to use these technologies in a meaningful way after 2015. The legislation is known as Health Information Technology for Economic and Clinical Health Act (HITECH). This will hopefully drive improved communication between healthcare providers.
The HITECH approach will likely increase "participatory medicine" where information on the patient's observation of their own symptoms and information on their environment, lifestyle, diet and family history will be included in the database.
The data will include disease and drug-gene data. For instance, right now, there are some cancers for which their genetics can be used to choose the best potential drug treatment. Not all tumor genetics have been identified, but imagine a patient has the genetic information for their tumor in the database. The clinician can look at that information relative to the patient's genetics and potential drug therapies.
The data connecting the correct drug with the disease is the basis of personalized medicine. Much of this will come from clinical studies where subpopulations are identified that respond to a given drug. When a patient has the same or very similar genetics as seen in a given subpopulation, the drug therapy can be narrowed down, for instance a drug may be chosen for the treatment of breast cancer due to the presence of overexpression of estrogen receptors (ER+ disease). This is a subpopulation of all breast cancers. Specific genetics of a cancer may be used to further specify treatment for a given individual.
Pharmacists will be at the forefront of data interpretation and application. Right now, pharmacists are receiving data from genetic laboratory tests and applying the information clinically. Many institutions, including St. Jude research hospital, University of Florida, Vanderbilt, Scripps Health, St. Rita's, and elsewhere are routinely using this data.
In the future you will use the data in your local drug store. It is becoming a standard of care.
OK, I would like responses here: Would you provide your saliva for DNA testing to be put into a database for reference when needed? If so, why, if not, why not?
By DFK | April 09, 2013 at 08:42 AM EDT | 6 comments
JES, like all individuals can have variation in response to a drug. The variation can be a result of an altered protein, drug target, including drug receptors, transporters, and drug metabolizing enzymes.
The drug receptor as a target is related to pharmacodynamics in that variation in the receptor will change how a drug affects the body, i.e. response.
The drug transporter as a target is related to pharmacokinetics in that variation in the transporter will change how the body affects the drug, with an example being drug distribution.
The drug metabolizing enzyme as a target is also related to pharmacokinetics in that altered metabolism changes what the body does to the drug. We have seen a number of examples with JES.
OK, let's see if we can provide some examples of drug targets, i.e., receptors, transporters, and drug metabolizing enzymes. See what you can offer here. Take a bit of time and do a little searching to identify some of each.
By DFK | April 02, 2013 at 08:56 AM EDT | 7 comments
Remember the rs number information (March 12 post), where the rs number is a unique and consistent identifier of a given SNP as found in the National Center for Biotechnology Information (NCBI; dbSNP) database? Well, JES has another rs number related to drug metabolism. This time, it is rs762551. I don't know if I posted this earlier...I could look, but it does not hurt to post this a second time. I am talking about the evidence level to back up some of the SNP information.
The Pharmacogenomics Knowledge Base (www.pharmgkb.org) provides the level of evidence related to specific SNPs. What are your thoughts about rs762551 in JES?
I should add JES's genotype (remember one from each parent) is CC.
By DFK | March 22, 2013 at 12:48 PM EDT | 2 comments
Ok, so how can an individual's DNA affect another individual? It is not like DNA is 'contagious'...or is it? While the current post is not related to JES, it presents a very clear example of the consequences of an individual's genotype. Here, we are not talking about a hereditary issue, but a drug metabolizing issue. Click HERE and read this interesting story about a potentially devastating gene-drug interaction. This is also not about clopidogrel, but there is an ultrarapid metabolizer (UM) connection. This post is FYI...no need to necessarily comment.
So, JES has DNA from his parents that imparts increased metabolism for drugs that are metabolized by CYP2C19 (See the March 12 post). When considering clopidogrel, the prodrug, JES readily converts the inactive drug to the active drug. JES's *17/*17 genetics is relatively rare. What is a more common variant is the *2 form. rs4244285, where A replaces G The *2 form of the gene results in a loss-of-function enzyme and clopidogrel will not be converted via CYP2C19 to its active form.
To compare the genetics of different forms of the CYP2C19 gene, I thought I would provide my data and directly compare it with JES's. Here, let's 'just say' that JES and I are have both underwent procedures to place stents (tubes) in our heart arteries to keep blood flowing and that we are to be given clopidogrel to prevent a clot from forming where the stent is:
JES *17/*17 - converts clopidogrel to active form, likely efficacious with respect to preventing a stent clot, although there is an increased risk of bleeding.
DFK *1/*2 - converts some clopidogrel to active form, increased risk of clot forming and of adverse cardiovascular events and death as studies show the *2 form imparts risk.
JES can remain on the drug, while DFK should be switched to an alternative antiplatelet therapy.
This is how genetic information in the context of personalized medicine can be utilized. Care can be improved through personalized medicine by:
- Identifying the correct drug to be given at the start of therapy
- Identifying a treatment that will avoid adverse reactions
- Increasing the patient's adherence to their medication therapy.
CYP2C19 *1/*1 (one from each parent) is the most common form and means an individual will convert clopidogrel to its active form. The *1/*1 individual is called the 'wild-type' and is an extensive (normal) metabolizer (EM). The *1/*2 individual, like me is an intermediate metabolizer (IM), the *2/*2 individual is a poor metabolizer (PM), while the person who is *17/*17, like JES is an ultrarapid metabolizer (UM).
See if you can tell us, with a noted citation of where you found the information, what the following individuals are considered relative to being an EM, IM, PM, or UM:
Yesterday in The Wall Street Journal, an article appeared entitled 'Plavix Disclosures are Probed'. Here are two portions of the Monday March 11, 2013 article by Peter Loftus:
'In 2010, the U.S. Food and Drug Administration added a boxed warning to the prescribing label for Plavix about the potential for reduced effectiveness in a subgroup of patients who metabolize the drug poorly.'
'At least two state attorneys general...have alleged that the [manufacturers] should have known since 2003 that Plavix has reduced effectiveness in patients who metabolize it poorly. The suits allege the companies failed to disclose that information in a timely manner because they wanted to preserve Plavix sales.'
This article brings up the whole issue of metabolizer status or metabolizer phenotype. The phenotype is the 'expression of an individual's physical trait or physiologic function due to genetic and environmental and other factors.' Here, we will focus on the genetic influence.
Plavix (clopidogrel) is a prodrug, meaning it must be converted to an active form to work. The enzyme responsible for this conversion is CYP2C19 and the following information is related to this enzyme. Individuals who are 'normal' metabolizers (with a normal gene from each parent) are also called extensive metabolizers or EM. People who get one common, normal gene from a parent and one loss-of-function gene from the other parent are heterozygotic (a different form from each parent) from the genetic sense and are considered 'intermediate (IM) metabolizers'. Individuals with two loss-of-function forms are considered 'poor metabolizers (PM), being homozygotic (same form from each parent) in the genetic sense. It is this population that is referred to in the Wall Street Journal article. Some individuals have increased metabolism and are considered 'ultrarapid' metabolizers.
The following are some thoughts about clopidogrel and the metabolizing phenotype. Also, the "star" nomenclature is provided as example genetic 'constitution' called the genotype:
EM (*1/*1 genotype) - normal dose of clopidogrel should provide therapeutic benefit
IM (*1/*2 genotype; there are others that cause a person to be an IM) - normal dose of clopidogrel may not provide therapeutic benefit to patients who have undergone stent (small tube) placement in the coronary arteries of the heart. While a larger dose would theoretically be needed so more drug could be converted to the active form, these individuals should be switched to a different therapy.
PM (*2/*2 genotype; there are others that cause a person to be a PM) - a different drug should be used for these individuals.
UM (*17/*17 genotype) - normal dose of clopidogrel should provide therapeutic benefit. There may be an increased risk of bleeding.
So, what does JES's data show? The 23andMe report states ‘Clopidogrel (Plavix®) Efficacy’. OK, to me this implies that JES is an EM, with a *1/*1 genotype having received the ‘normal’ CYP2C19 gene from each parent, i.e. no SNPs. Digging a bit deeper, here is the information I found:
JES in fact has a SNP, rs12248560. The rs number is a unique and consistent identifier of a given SNP as found in the National Center for Biotechnology Information (NCBI) database. In this case, the rs12248560 refers to T replacing C at a specific location on the CYP2C19 gene. Not only did JES have a T at that position from one parent, he had a T at that position on the gene from his other parent...making JES a *17/*17 ultrarapid metabolizer!
Now remember, relative to clopidogrel, a UM will readily convert the parent (inactive) compound to the active form. This active form is the therapeutic beneficial form.
Here is a challenge. Consider drugs that are active as the parent compound (i.e., not a prodrug). Tell us what may be the expectation for effectiveness of drug therapy with other drugs metabolized by CYP2C19 in JES.
The link takes you directly to a Landmark Case. Scroll up and down the page to get some history relative to discrimination based on genetics. There is some important information here. Make sure you read the section on the discrimination example of the Burlington Northern Santa Fe Railway.
By DFK | February 19, 2013 at 06:40 PM EST | 16 comments
We have observed the relative risk (increased or decreased) related to diseases and will soon start the discussion on genetic variation related to drug response. First, however, let's talk about all the components that must work together to make personalized medicine (PM) move forward. As you can see, I have termed these the 'cogs' and 'sprockets'. As with any 'fine-tuned' machine, all of the parts must work together and they all have a critical role to play.
It was the rapid progress made with technology (technology and tools) that has brought personalized medicine closer to clinical implementation. The DNA sequencing technology progress has resulted in the cost of whole-genome sequencing to drop, now, close to the 'magic' value of $1000. There was no single study that made this happen...it was the Human Genome Project (HGP) that was the driving force for the lightning-speed advancement in technology that has moved pharmacogenetic testing into some clinical settings at this time. The technology is just one 'cog' or 'sprocket'. What other components will make the (PM) run like a 'well-oiled' machine?
Regulation: The regulatory agencies must provide guidance that will facilitate PM moving forward, such as supporting co-development of drugs and genetic markers related to drug response.
Insurance coverage and reimbursement: When validated and used appropriately, insurers and government programs must be willing to pay for genetic testing as they would other laboratory tests.
Genetic privacy and legal protections: Just as HIPAA has now been a standard, so has the Genetic Information Nondiscrimination Act (GINA), preventing discrimination by employers and health insurers based on genetic information. There will be broader ethical and legal protections as we move forward.
Medical education: All healthcare providers will need to understand the intricacies of genetics related to drug response. The education must be broad to cover all of the other 'cogs' and 'sprockets'.
Healthcare information technology: With all of the data that is produced by the sequencing technology, the infrastructure must be put in place to move raw genetic data to the user in an end-user format.
These are just some examples for each of the components. Now, let's discuss these different components. Please comment on any of the components you wish to discuss. Offer some ideas, concerns, and insight about these. Let's hear your thoughts!
By DFK | February 12, 2013 at 09:12 AM EST | 28 comments
Alzheimer's Disease - The neurodegenerative disease that leads to a loss in the ability to function, even at the simplest level. Would you want to know if you were at a relative increased risk of the disease? Would you want your children to know? After all, you pass your genetic information on to them.
What if your health insurer found out that you had an increased risk? There are some legal protections in place to help prevent discrimination. The Genetic Information Nondiscrimination Act (GINA) protects individuals from discrimination based on genetics by employers and health insurers.
Here is what JES found:
Alzheimer's Disease JES risk 14.2% Average risk 7.2% 1.98x
JES has one copy of the ε4 variant, which imparts an increased risk. This genetic information, like all genetic information and unlike most laboratory data will not change over a person's lifetime. Whether talking about disease or a response to a drug. Your genetic information does not change over a lifetime. If you have the ε4 it will not go away.
Consider the questions above questions. Personally, this would be a difficult one to answer.
By DFK | February 08, 2013 at 03:12 PM EST | 20 comments
As stated, 23andme provides "Disease Risk" information. The previous post was related to the relative risk of rheumatoid arthritis. Below is an image form the 23andme results. Again, relative risk of certain diseases. These relative risks need to be put into context. So look at the information and comment on the "context" of the risk. Let's be as broad thinking as possible and don't be afraid to comment about anything...
What would you think if this was your disease risk profile. The next post will be a big one regarding a very 'charged' topic...stay tuned!
By DFK | February 05, 2013 at 06:36 PM EST | 15 comments
This is a previous post from last year, modified a bit to get everyone on the “same page”. With the many different people reading this blog, I thought it best to have a baseline with the discussions starting with the disease risk information. (Please note that this is generalized for folks who do not have a background with this information. Also, while the results presented below are from 23andMe, the rest of the information was taken from various sources.)
The human genome is made up of a sequence of four chemicals, called nucleotide bases, and includes adenine (A), guanine (G), thymine (T), and Cytosine(C). This sequence is our DNA and it is found in almost every cell of the body on 23 chromosomes. We get a set of chromosomes from each parent, so there are 46 chromosomes in each cell (23 pairs). The sequence of DNA from each parent is about three (3) billion bases long...the four chemicals in a long sequence. Based on DNA we are about 99.9% the same. Differences between individuals can be described as genetic variation. In some cases the genetic variation can be a result of a change in the sequence by one nucleotide base replacing another, such as an A replacing a G. For instance:
A sequence that is the most “common” sequence may be TCC AAG CTG GAA TCC GGT GTC
The variation may be: TCC AAG CAG GAA TCC GGT GTC, where A (adenine) replaced T (thymine).
This is called a single nucleotide change or single nucleotide polymorphism (SNP, pronounced “snip”), since one chemical replaced another. At a given point on each chromosome, there is a specific nucleotide base. Remember that each parent contributes 23 chromosomes, so there are two sets of chromosomes. At a given point on each chromosome is a nucleotide base from each parent. The pair of bases is called a genotype. A SNP can occur at a given point on the chromosome from either or both parents. The change(s) may result in a difference from one individual to another. We will have some examples of this over the coming weeks.
Disease Risk: The 23andMe information provides data about increased risk of disease, average risk of disease and decreased risk of disease. Here, the risk is a RELATIVErisk. Let’s start with increased risk of disease. According to 23andMe, JES has 1.54 times the average risk of getting rheumatoid arthritis (RA).
How was this information provided to JES? Through what is called the “odds calculator”, where 3.7 men with a genetic make-up like JESs’, according to 23andMe may develop RA where as with average risk 2.4 men out of 100 may develop the disease. The 1.54 times the average risk value is simply 3.7 divided by 2.4.
So what is the genetic basis for this increased relative risk of getting RA? There are eight SNPs (snips) that have been associated with the risk of RA, in individuals with a similar ancestry to JES. Below are JES’s genotypes for each of the eight SNPs related to RA:
SNP1 genotype TT; 1.95 times the average risk – increased risk
SNP2 genotype GG; 0.79 times the average risk (less than 1 means decreased risk) – decreased risk
SNP3 genotype CT; 0.92 times the average risk – decreased risk
SNP4 genotype AA; 0.93 times the average risk – decreased risk
SNP5 genotype AG; 0.97 times the average risk – decreased risk
SNP6 genotype GT; 1.13 times the average risk – increased risk
SNP7 genotype AA; 1.04 times the average risk – increased risk
SNP8 genotype GT; 1.03 times the average risk – increased risk
To put the above data into context, multiple large studies identified relationships between the specific SNPs and the risk of RA. Taking into account the SNPs that are related to increase risk, again relative risk of RA (numbers 1, 6, 7, and 8) and those that are related to decreased risk (numbers 2, 3, 4, and 5) result in an overall increased risk of 1.54 times the average overall risk. This data is based on information from individuals with a similar (European) ancestry to that of JES. Specifically the data comes from two studies including thousands of patients with RA and also thousands of “control” patients without the disease.
What does this mean to JES. Does this mean he will get RA?
Again, we have such a diverse audience reading this. I hope that the presentation of the information makes sense. There is a great deal of work that needs to be done to understand JES’s relative risk as presented in his data. Most individuals will look only at the summary data and not look at this technical level. Again risk does not mean it will happen. The genetic-based risk must be looked at in the context of overall risk that includes diet, and the environment among other potential risk factors.
By DFK | January 29, 2013 at 09:27 AM EST | 23 comments
There is considerable information provided by 23andMe for the testing and test result interpretation. As we have already discussed, and as you will see, I have concerns about how the provided information is viewed and understood. What information should 23andMe provide? When is a little information not enough and at what point is the information "too much". Below are some section headings from the "Terms and Conditions", which acan be accessed on the 23andme.com website:
Risks and Considerations Regarding 23andMe Services:
- Once you obtain your Genetic Information, the knowledge is irrevocable.Comment: There are some results with more substantiation than others. While some of the data presented is supported by multiple relatively large studies, other results are based on considerably less data. This is stated on the site.
Two BIG questions here;
Should results be presented that are not supported by multiple large studies?
and a BIGGER question;
Should results be provided that have no actionable response? i.e., disease information for which there is no treatment.
Please give us your thoughts on this one in particular. Also, keep this in mind as we start into the disease risk data.
- You may learn information about yourself that you do not anticipate.Comment: This is part of the intrigue of personal genome testing. I know this was a motivating factor for JES.
- You should not change your health behaviors solely on the basis of information from 23andMe.Comment: If JES has a reported increase risk for a given disease, will he try to change the other risk factors he can change?
- Genetic research is not comprehensive.Comment: This is not a sequencing of JES's entire genome...just bits and pieces of which some may be more important than others.
- Genetic Information you share with others could be used against your interests.Comment: Please don't use this information against JES! I know this is not an issue in this setting, but it can be for some.
There is a lot of information you can get from their website (again, not an endorsement;click here). The disclaimers are there, but so is the plethora of information. It can be a lot to try and digest for the average individual. I see the questions coming to healthcare providers.
Later this week, we will start looking at the disease risk information.
By DFK | January 24, 2013 at 09:32 AM EST | 30 comments
To continue with more 'trait' information, not provided on the 'About JES' page. There were a number of, what I will call 'disease resistance' traits. Here are the reults for JES:
Malaria resistance - not resistant
Resistance to HIV - not resistant
While JES's results indicate he is not resistant, how do think this kind of information may impact an individual if the results were noted as resistant (to malaria and/or HIV)?
Interestingly JES traveled to Ghana recently. Malaria has a major prevalence in Ghana. JES received all of the prophylactic medicine to help prevent contracting malaria and did not get the disease. If he was resistant should he have approached the prophylactic treatment differently?
Think 'broadly' here. Think about all the different types of people you know. How do you think they would use this resistance data?
By DFK | January 22, 2013 at 09:42 AM EST | 28 comments
I explained to JES, our 'DNA data donator', how I went about getting my DNA tested last year and how I intended to use the data as the basis for an elective course called 'personal genome evaluation'. I knew that if we offered this course again, that we would need a different set of data to look at...so, JES offered his DNA data. We will get to JES's information soon.
As I posted last year and have now 'edited', I now describe what JES did to get his DNA tested.
JES went online, and reviewed the 23andme procedure for providing a DNA sample. He, picked the service and paid via credit card, then waited for the kit to arrive. In about a week, he received the test sample kit and promptly read the directions. Following the directions, JES provided a saliva sample of about 5 mL, a teaspoonful, which took about five minutes of spitting into the tube to obtain this volume. The tube cap had a preservative that automatically mixed with the saliva when the cap is screwed on the tube and the 'snapped' closed. JES inverted the tube a number of times to mix the saliva and preservative. At this point he replaced to first cap with the shipping cap. He placed the capped tube with the saliva sample in the provided zip-lock 'bio-hazard-bag' and placed that into the already addressed return container.
The fact that saliva was used is key to a consumer product. With DNA in every nucleated cell (i.e., cells with a nucleus) of the body I guess it really doesn't matter what sample you provide...I just do not see the public drawing a blood sample and getting white blood cells that way (remember red blood cells won't help here...no DNA)! And, I, and others would struggle supplying a sufficient hair sample!
JES and I discussed the 'point of no return' point, i.e., putting the shipping carton with the saliva sample in the mail. JES did not hesitate at all. He had seen my data and wanted to see his. He would receive information about his physical traits, risk of disease, 'drug sensitivity', and disease carrier status. JES and I discussed his deciding to get his DNA tested and I thought 'go ahead the DNA is there regardless of whether or not you know what is says'. This is the same thing I thought about my own testing last year. So, into the mailbox it went.
It did take about a month for the results to be made available to JES via the 23andme.com website.
We are going to start with the simple things, what JES's DNA states about his physical traits. Take a look at 'About JES'. Check the link on the menu at the left. A question comes to my mind right away: 1. I have seen JES sneeze when he is in the sun light. I don't think it is just the occasional sneeze. Anyhow, look at his trait information and I will add one more here...JES has a lower tendency to overeat...wish I did!
So, to get started just look at JES's traits. I will say that his genetics do not exactly match his expressed traits (phenotype). Why would this be possible? Go ahead and post your thoughts!
By DFK | January 04, 2013 at 01:25 PM EST | 5 comments
This entry is modified from the original post in January of 2012. It is in reference to our "guest DNA provider", JES.
Why is this blog here? With the responsibility of keeping our students on the forefront of pharmacy education, I felt obligated to present, from a public point of view, where "things" are at with personal genetic information. As I have talked about patients who eliminate drugs from their body slowly (poor metabolizers) versus those who remove drugs rapidly (extensive and ultra rapid metabolizers) in class for years, I felt that this needed to be placed in the context of the "bigger picture". With the advent of direct to consumer (DTC) genetic testing, I saw the opportunity to investigate the "bigger picture".
JES sent his DNA sample (saliva) to arguably the most commercial of the DTC "personal genome" companies so we could delve into his personal genetic information.
Being in pharmacy education, we specifically were looking at this information to see the drug-genetic connections (pharmacogenetic) side of things. We wanted to know how JES "handled" certain drugs. This term, pharmacogenetics was defining what we wanted to know. That is, we wanted to study JES's genetic makeup in order predict how he would respond to certain drugs and to understand how certain drugs should be prescribed for him.
So, we are checking JES's pharmacogenetics, hence this PGxCheck.com blog...but it is much bigger than just drug response. We will learn what disease risk JES has, what disease(s) He may be a carrier of and what his DNA says about physical traits. The bigger picture includes legal issues, such as discrimination, ethics, healthcare, business and broader personal questions. We all need to be thinking about the use of genetic information in this era of easy access to DNA information.
We will start with the traits JES's genetics says he has. Certainly, he knows how he expresses some of the defined traits. It will be interesting to see if JES's expression of the traits, his phenotype, matches what his genetics say he should express as a trait, his genotype.
To get us all at a starting point, click on “About JES” at the left. You will see the trait that was tested by the personal genome company, how JES expresses that trait and we will start looking at the results and enter the results from JES's DNA testing. We will see if they match…and discuss why they may not!
For the students that are following along, I will also send an e-mail when there is a post.