Case 2: Genetic testing to support pharmacogenetic-based drug dosing

The goal of this case study is to show you how to find information to support medication selection and/or dosage for a specific patient based on the results of their genetic test results.

Approach/Workflow

Workflow for pharmacogenomics analysis: Medgen, GTR, Test Result examination, ClinVar, Medgen

Welcome to Your Patient!

Charlotte, 52 year old female, was referred to you....

Upcoming Procedure: Angioplasty for treat Acute Coronary Syndrome

Charlotte was diagnosed with Acute Coronary Syndrome, scheduled for an angioplasty and informed that she would need to take clopidogrel (a.k.a. Plavix^®) for at least 3-6 months. She mentioned that her father died of a stroke while taking the drug and was worried about her own situation. You should consider pharmacogenetic influences on clopidogrel response in this patient to see if a change in the prescription should be recommended.

(P.S. She's doing great and has changed her approach to life with diet, exercise and a mental wellness plan!)

Learn more about Charlotte's potential clopidogrel issue

To learn more about factors that may impact response to clopidogrel (Plavix^®), search MedGen (https://www.ncbi.nlm.nih.gov/medgen/) with:

clopidogrel response

If you need it, you can click here to get to a link for the Medgen record page.

Try this!

There is a Gene identified near the top of this record, which one?

Scan the Description section with information from PharmGKB to learn how clopidogrel response issues may arise.

There are other great sources of information in the Additional descriptions section: a summary from the Medical Genetics Summaries.review article and from the MedlinePlusGenetics reference.

What is the concern for genetic variant influence on clopidogrel response?

To learn more about factors impacting clopiogrel response, you can link to:

- - - Medical Genetics Summaries to learn about patient response issues based on their CYP2C19 genotypes.

Note: Medical Genetics Summaries is growing collection of summaries coordinated by the NCBI/NLM which describe the impact that specific genetic variations have on developing a disease or responding to a specific drug. It is a very helpful review article type of resource, and is thus featured in it's own section on relevant MedGen records. You should consider accessing and reading the whole article!

- - - In the Clinical resources section (on the right), clicking on PharmGKB will take you to a comprehensive reference source for pharmacology, clinical annotations, as well as prescribing and drug label information,

What to take into consideration for ordering a Genetic Test.

- - - Pros
      - Genetic tests are decreasing in cost & are not particularly invasive.
      - A well-known genetic lesion can sometimes help in predicting drug response issues and may be annotated with guidance on adjusting dosage or switching to an alternative therapeutic.
      - A finding may predict an issue before adverse event symptoms begin for proactive & preventative care.
    - Cons
      - We are early in our understanding of genes, gene variants and disease: Failure to detect a pathogenic variant does not rule out a potential problem.
      - Prediction isn’t guaranteed as pathogenic variants sometimes do not cause the same issue in all patients (penetrance, severity, multi-genic & environmental influences).
      - Lack of coverage by some insurance companies…

Find a genetic test to order and examine the results

If you need it, you can click here to get to a link for the Medgen record page.

Try this!

2. In the Genetic Testing Registry section of the MedGen record (on the right), click on the See all link to retrieve information on all of the genetic test information that has been submitted to us by providers for this disorder or condition.

To narrow the list to the most relevant tests, use the sidebar filters (on the left side) to focus on one(s) from a Missouri-based, CLIA-certified clinical lab.

Click on the lab test title to learn more about the genetic test including "How to Order" it and often the "Methodology" employed for the test. Explore the information provided.

Note: The information shown in the NIH Genetic Testing Registry (GTR) is submitted by the testing laboratory. If you have any questions, you should click the "Laboratory Contact" tab for ways to contact them directly.

3. You ordered the test, it was performed, and the genetic test results have come back from the lab!

Hyperlinked icon for a genetic test result

Note: There is currently no established standard format for the results. Each laboratory creates it's own report - some are very detailed, some pretty terse. We are providing you an example format.

What is/are the specific gene(s) and variation(s) identified in Charlotte?
There are two different nomenclatures used, what is it also called?

What does the genetic test report assert for Charlotte's likely response to clopidogrel?

How does this relate to what you read ion the MedGen record - in the PharmGKB and Medical Genetics Summaries synopses?

Validate the genetic test result assertion and find more information about a genetic variant

4, To validate what is asserted by this clinical testing laboratory, search NCBI’s ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) with:

Cyp2C19 p.Trp212Ter

If you need it, you can click here to get to a link for the ClinVar record page.

Try this!

What does the ClinVar record indicate in the Clinical Significance field for this genetic variation?

To learn more about this, click the hyperlinked Variation location.

Important! Assertions about the clinical significance or interpretation are provided to NCBI by submitters. All those who have provided information are listed in the Submitted interpretations and evidence section of the record, so that you can look at them all and learn more about what each submitter provided.

In addition to links in the Submitted interpretations and evidence table, the ClinVar record provides additional Citations for this variant - links to key PubMed records as well as other helpful resources.

Find genotype-based actionable information

5. To find recommendations for a how Charlotte's genotype may require a shift in case management, go back to the MedGen page.

If you need it, you can click here to get to a link for the Medgen record.

Try this!

< Perhaps the most helpful and direct information may be on the curated drug label provided in the Practice Guidelines or Professional Guidelines sections from the NLM's DailyMed.

However, more detailed information can be found in the Therapeutic recommendation section with synopses from a number of helpful sources, including:

- - - - a US Food and Drug Administration (FDA) statement
      - a statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
      - a summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

- - - And a link to the Medical Genetics Summaries review article with all of the details.

Now that you are a-ground....What to consider when discussing the results of a Genetic Test.

- - - Clinically, what do you do with this information?
      - Hopefully, you already knew what to do with the information (potential impact of a genetic variant on the patient’s physiology and phenotype and how this relates to your choice of case management) – before the test was ordered.
      - A patient may ask: “What is wrong with me and how can we fix or deal with it?" A great reason to consult with a Genetic Counselor!
    - Outside of this planned clinical event: A patient may ask: “What do I (we) do now?”
      - Implications for the patient - beyond this particular event: Consider having them discuss this with their primary care physician, dentist, and any other clinical professionals who may need to know for their care.
      - Implications for the patient’s family members: Should they tell others?

Find Patient Education materials to share with the patient and her family

To assist you further in your communications with Charlotte and her family about this disorder, there are links to some helpful documents on the MedGen page.

Depending upon their level of interest and knowledge, you may wish to share:

- - Professional literature such as the Medical Genetics Summaries review article or one of the Reviews in PubMed.
  - For a more lay audience, you could find information in MedlinePlus (link) or MedlinePlus Genetics (link)

Charlotte was aware of her father's adverse events with clopidogrel and was able to ask questions during her own care. The impact of a person's genetics on drug response is something many patients have not heard about. You discuss the results of the genetic test and let her know that you are recommending a change in prescription. You also provide patient education materials can be helpful for her to learn about the importance of this topic for her own health care.

In addition to her own situation, Charlotte is concerned about the implications of this clopidogrel response issue for other members of her family. She would like to know if this might impact the efficacy and safety for other medications they may be prescribed.

Case Recap

This case study demonstrated how genetic testing can be helpful to identify those with potential problems in drug response which could ultimately cause severe adverse events in people like Charlotte (an her father).

Case management for the disorder
- Charlotte's drug metabolism may be compromized.
  - Based on her genotype, Charlotte (and likely her father) are classified as Poor Metabolisers with regard to clopidogrel.
  - Clopidogrel is a pro-drug and needs to be activated for full potency to prevent overclotting by inhibiting it's target - the P2RY12 receptor which plays a central role in platelet activation and recruitment of other platelets for clotting.
  - If clopidogrel is not activated, as in the case of poor metabolizers, the P2RY12 receptor continues to promote platelet aggregation and blood clot formation which can lead to heart attacks, strokes, and thromboses in individuals with a history of these conditions.
- Therefore, clopidogrel should be avoided and instead an alternative drug which is not activated by CYP2C19 should be prescribed, such as prasugrel or ticagrelor.

In this particular case, the diagnosis may have ramifications on healthcare beyond this procedure, for example:

As Charlotte already noted, certain medications may pose a much greater risk to her and members of her family who have inherited the same genetic variant.
Therefore, they may want to inform other healthcare practicioners who may prescribe drugs impacted by CYP2C19 variants (PharmGKB & CPIC Guidelines)

As happened in this case, discussing this inherited disorder with family members may prevent other potentially catastrophic events in the future for his loved ones. Though discussing these topics can be difficult, reaching out to a Genetic Counselor may be particularly helpful for these conversations.

Take-away Message!

This case study was an example of how pharmacogenetic testing might be able to provide critical information to optimioze case management plan for a particular patient based on their genetics. It also showed that understanding a patient's particular risk may have wide implications for both themselves and their families and could help to inform health and medical care long-term.

Last Reviewed: April 18, 2023