I have stars in my genome! How genetic variations affect your drug response

Many common medications work well for most people but cause side effects or do not work for others. One important reason is genetics. Small differences in your genes can change how quickly your body breaks down a medication, how much of it reaches your bloodstream and how well it works. If you have had a pharmacogenetic test, your results may list your genes with "stars", such as CYP2C19 *1/*17. This article explains what those stars mean and how they help you and your prescriber choose the right medication and dose.

How does your body handle a medication?

After you take a pill, your body absorbs it, carries it in the blood to where it acts, breaks it down (metabolism) and removes it, mostly through the liver and kidneys. Doctors call this process pharmacokinetics.

Imagine your body is a swimming pool. Each dose you take is water flowing in, and the water level is the amount of medication in your blood. Your liver and kidneys are the drain. For a medication to work safely, the water level needs to stay in the right range:

• If the drain is slow, the water rises too high and the medication can build up and cause side effects.
• If the drain is fast, the water stays too low and the medication may not work.

Your genes help set the speed of the drain. Age, liver and kidney health, alcohol, smoking, diet and other medications can change it too.

Which genes affect how medications work?

The most important genes are those that make the liver enzymes called cytochrome P450 (CYP for short), such as CYP2D6, CYP2C19 and CYP2C9. Together these enzymes break down a large share of commonly prescribed medications. Some medications are inactive when you take them (prodrugs) and need a CYP enzyme to turn them into their active form.

Other genes matter too. Some control transporters that move medications into and out of cells, such as SLCO1B1 for some statins. Others affect the target a medication acts on. The study of how genes affect your response to medications is called pharmacogenetics.

What are "star alleles"?

You inherit two copies of each gene, one from each parent. Each version of a gene is called an allele. For pharmacogenes, alleles are named with a star and a number, such as *1, *2 or *17. The official catalogue of these names is kept by the Pharmacogene Variation (PharmVar) Consortium.

Two points help when reading your results:

• *1 is usually the reference version, which works normally.
• The other numbers show the order in which the versions were named, not how they work. A higher number does not mean a rarer or more harmful variant. For example, CYP2D6*2 works normally, while CYP2C19*2 does not work at all. CYP2D6*41, which reduces enzyme activity, is one of the more common CYP2D6 variants worldwide.

Your result is written as a pair, one allele from each parent, such as *1/*2. This pair is called your diplotype.

How do your stars become your metabolizer status?

Each allele has a known function: normal, decreased, increased or no function. The combination of your two alleles predicts your metabolizer status, using standard terms set by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Here is how it works for CYP2C19:

Your CYP2C19 result	What the alleles do	Metabolizer status
*1/*1	Two normal-function copies	Normal metabolizer
*1/*17	One normal and one increased-function copy	Rapid metabolizer
*17/*17	Two increased-function copies	Ultrarapid metabolizer
*1/*2 or *1/*3	One normal and one no-function copy	Intermediate metabolizer
*2/*2 or *2/*3	Two no-function copies	Poor metabolizer

For CYP2D6 and CYP2C9, each allele is given an activity value, and the two values are added to form an activity score. For example, CYP2D6*1 counts as 1 and *41 as 0.5, so *1/*41 adds up to 1.5, which is a normal metabolizer.

What if you have extra or missing copies of a gene?

Most gene variants change a single letter of DNA. Some are larger changes in the structure of a gene, called structural variants. The most common are copy number variants, where a person has more or fewer than the usual two copies of a gene.

CYP2D6 is the key example:

• Deletion. Some people are missing a whole copy of CYP2D6 (written as *5). A *5 copy makes no enzyme.
• Duplication. Others carry two or more copies of CYP2D6 on the same chromosome (written as, for example, *1x2 or 3N). Extra working copies add to the activity score and can make a person an ultrarapid metabolizer. The share of ultrarapid metabolizers ranges from about 1% to 21% across world populations and is highest in some Middle Eastern, North African and Oceanian populations. A duplicated copy that does not work, such as *4x2, does not add any activity.
• Hybrid genes. CYP2D6 sits next to a similar, non-working gene called CYP2D7. Pieces of the two can fuse into hybrid alleles, such as *13, *36 and *68, which make little or no working enzyme.

Other genes that affect medications can also be deleted or duplicated, such as CYP2A6, which breaks down nicotine. Copy number matters because it can change your metabolizer status. For example, a CYP2D6 ultrarapid metabolizer may turn codeine into morphine too quickly, while a person with a deletion may get little pain relief from it. A test that only looks for single-letter changes can miss a missing or extra copy and report the wrong status, so ask whether a test checks CYP2D6 copy number.

What does your metabolizer status mean for your medications?

The same metabolizer status can mean opposite things for different medications. CYP2C19 is a good example:

• Clopidogrel (Plavix) is a blood thinner that CYP2C19 must activate. Intermediate and poor metabolizers make less of the active drug, so it protects them less well, and they have a higher risk of heart attack and stroke. For people with heart disease, especially after a stent, and for some stroke prevention, CPIC recommends another antiplatelet drug such as prasugrel or ticagrelor where appropriate. Normal, rapid and ultrarapid metabolizers can take the standard dose.
• Proton pump inhibitors (PPIs) such as omeprazole and pantoprazole, used for heartburn and ulcers, are inactivated by CYP2C19. Poor and intermediate metabolizers keep higher levels, so the drug works well for them, and a lower dose may be considered for long-term use. Ultrarapid metabolizers clear PPIs quickly, so CPIC recommends doubling the starting dose, and rapid metabolizers may need a higher dose for some conditions.

Genes can affect more than medications. In one study, people with a slower-acting version of the CYP1A2 gene, which breaks down caffeine, had a higher risk of a non-fatal heart attack when they drank two or more cups of coffee a day. People with the faster-acting version did not.

Your genes are only part of the picture. Your prescriber also considers your age, weight, kidney and liver function, other medications and your health history.

How can a pharmacogenetic test help?

A Pillcheck test reports your star alleles and metabolizer status for genes such as CYP2D6, CYP2C19, CYP2C9, CYP1A2 and SLCO1B1. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. A Pillcheck pharmacist reviews your results together with your current medications and explains what they mean in plain language, with recommendations to discuss with your prescriber. Your results last a lifetime and can guide future prescriptions too. Read more about how to get a pharmacogenetic test in Canada.

Summary

• Your genes affect how your body absorbs, activates, breaks down and removes many medications.
• Gene versions are named with stars, such as *1, *2 and *17. The number shows the order of naming, not how the gene works.
• Some people have extra or missing copies of a gene, especially CYP2D6. These copy number variants can change your metabolizer status.
• Your two alleles together predict whether you are a poor, intermediate, normal, rapid or ultrarapid metabolizer.
• The same status can call for a different drug for one medication and a different dose for another.
• A pharmacogenetic test, reviewed by a pharmacist, helps you and your prescriber choose the right medication and dose.

Frequently asked questions

Is *1 always the "normal" version of a gene?

In most genes, *1 is the reference version and works normally. Other alleles can also work normally, so always look at the reported function or metabolizer status rather than the star number alone.

Does a high star number mean a rare or dangerous variant?

No. Numbers are given in the order the variants were named. Some high-numbered alleles, such as CYP2D6*41, are common.

Can my metabolizer status change over time?

Your genes do not change, but some medications, smoking and health conditions can speed up or slow down your enzymes. This is why your pharmacist reviews your genetic results together with all your current medications.

Should I stop or change a medication based on my results?

No. Do not stop or change any medication on your own. Share your results with your prescriber or pharmacist, who can decide whether a change is needed.

References

Gaedigk A, Ingelman-Sundberg M, Miller NA, et al. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther. 2018;103(3):399-401.

Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19(2):215-223.

Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2020;13(1):116-124.

Nofziger C, Turner AJ, Sangkuhl K, et al. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther. 2020;107(1):154-170.

Gaedigk A, Sangkuhl K, Whirl-Carrillo M, et al. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69-76.

Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022;112(5):959-967.

Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clin Pharmacol Ther. 2021;109(6):1417-1423.

Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006;295(10):1135-1141.