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Key genes: CYP2D6, CYP2C19 and more

Reviewed by Dr. Daniel Wallerstorfer, molecular biologist and founder of Novogenia · Updated: 13 October 2026 · Reading time: 9 min

A few genes, many drugs

Picture the liver as a workshop where drugs are converted and disposed of. Every tool in it is built from a genetic blueprint. The remarkable thing: a handful of tools does a large share of the work – and their blueprints are exactly what pharmacogenetics focuses on.

A look at the guidelines of the international CPIC consortium shows this. Of the 29 guidelines CPIC lists as of October 2026, the CYP2D6 gene appears in 7, the CYP2C19 gene in 5 and the CYP2C9 gene in 4 (CPIC guidelines). Know these three genes, and you already have a large part of the guidelines in view.

The following genes are typical genes of pharmacogenetic panels. Which genes and variants a test actually covers is defined by each lab for its own panel.

CYP2D6: the workhorse with spare copies

CYP2D6 is involved in more CPIC guidelines than any other gene: opioids, antidepressants, tamoxifen, atomoxetine, ondansetron and beta-blockers. What makes it special: the gene can be missing or present in extra copies. Someone who carries three or more functional copies can convert codeine into morphine so fast that it becomes dangerous – as the Geneva case described in What is pharmacogenetics? shows.

How common are the types? For people of European ancestry, CPIC frequency data put CYP2D6 poor metabolizers at around 6.5% and ultrarapid metabolizers at around 2.3%. For codeine, the CPIC guideline advises against its use in both groups: in ultrarapid metabolizers because of the potential for serious toxicity, in poor metabolizers because of diminished pain relief (Crews et al., Clinical Pharmacology & Therapeutics, 2021).

Important for practice: CYP2D6 is genetically demanding. Labs usually read a selection of known variants; extra copies, hybrid genes and other structural variants are captured with varying precision, as the same guideline describes. So it is worth checking the result: which variants were tested, and was the copy number determined?

CYP2C19: key to clopidogrel and acid blockers

Clopidogrel is a prodrug: only CYP2C19 converts it into the active antiplatelet agent. Poor and intermediate metabolizers produce less of it. The CPIC guideline therefore advises, in acute coronary syndrome or percutaneous coronary intervention (PCI), avoiding standard-dose clopidogrel in these types where possible and – in the absence of contraindications – using prasugrel or ticagrelor at standard dose (Lee et al., Clinical Pharmacology & Therapeutics, 2022).

What this looks like in practice is shown by the POPular Genetics trial with 2,488 patients after primary PCI. In the genotype-guided group, carriers of a loss-of-function variant received ticagrelor or prasugrel, and everyone else received clopidogrel. For thrombotic events, this strategy was noninferior to standard treatment – and bleeding occurred less often: in 9.8% versus 12.5% (Claassens et al., New England Journal of Medicine, 2019).

With proton pump inhibitors such as omeprazole or pantoprazole, it works the other way around: here CYP2C19 breaks the drug down. The CPIC guideline names a higher starting dose for ultrarapid metabolizers and, for poor and intermediate metabolizers on long-term therapy, a possible dose reduction (Lima et al., Clinical Pharmacology & Therapeutics, 2021). According to CPIC frequency data, almost a third of people of European ancestry are rapid or ultrarapid CYP2C19 metabolizers, and more than a quarter are intermediate or poor metabolizers.

CYP2C9 and VKORC1: the warfarin duo

With the anticoagulant warfarin, two genes work together: CYP2C9 breaks it down, and VKORC1 is its docking site. The CPIC guideline describes how CYP2C9, VKORC1 and CYP4F2 results can be built into genotype-guided dosing to reach a target INR of 2 to 3 – with recommendations that differ by ancestry (Johnson et al., Clinical Pharmacology & Therapeutics, 2017).

CYP2C9 is also involved in guidelines on phenytoin, on nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib, flurbiprofen, meloxicam and piroxicam, and on fluvastatin (Theken et al., Clinical Pharmacology & Therapeutics, 2020). According to CPIC data, around a third of people of European ancestry are CYP2C9 intermediate metabolizers.

SLCO1B1: the entrance door for statins

SLCO1B1 is the blueprint for a transporter that brings statins into the liver – where they are meant to work. If the door works poorly, more statin stays in the blood. This was discovered in a genome-wide study of people taking 80 mg of simvastatin daily: a single locus stood out. The odds ratio for myopathy was 4.5 per copy of the variant and 16.9 with two copies; more than 60% of the myopathy cases could be attributed to the variant (SEARCH Collaborative Group, New England Journal of Medicine, 2008). The authors saw this as an opportunity to achieve the benefits of statin therapy more safely and effectively.

Today, for decreased or poor SLCO1B1 function, the CPIC guideline recommends choosing a suitable alternative statin depending on the desired potency or limiting the simvastatin dose (Cooper-DeHoff et al., Clinical Pharmacology & Therapeutics, 2022). According to CPIC data, decreased or poor function affects just under a third of people of European ancestry.

DPYD: the safety check before fluoropyrimidines

5-fluorouracil and capecitabine are among the most commonly used cancer drugs. They are broken down by the enzyme DPD, whose blueprint is the DPYD gene. If the enzyme is partly or completely missing, the drug stays active for too long, and severe side effects become more likely.

In the Netherlands, 17 hospitals tested patients for four DPYD variants before starting treatment. Of 1,103 evaluable patients, 85 (8%) carried a variant and received a reduced starting dose. The authors conclude that genotype-guided dose reduction improved the safety of treatment (Henricks et al., Lancet Oncology, 2018). The CPIC guideline names a starting dose reduced by 50% followed by titration for intermediate metabolizers and advises against these drugs in poor metabolizers (Amstutz et al., Clinical Pharmacology & Therapeutics, 2018). European product information addresses the topic too – more in Guidelines: CPIC, DPWG and drug labels.

TPMT and NUDT15: getting thiopurine doses right

Azathioprine, mercaptopurine and thioguanine are used in cancer treatment as well as to dampen the immune system, for example in autoimmune diseases. They are broken down by the enzymes TPMT and NUDT15. If their activity is reduced or absent, severe side effects such as pronounced bone marrow suppression become more likely at standard doses. The variants occur in all world populations, but their frequency varies by ancestry (Maillard et al., Clinical Pharmacology & Therapeutics, 2026).

Among people of European ancestry, CPIC data put around 9% as intermediate and about 2 in 1,000 as poor TPMT metabolizers. The guideline recommends lower starting doses for reduced activity and, for absent activity, strongly reduced doses or an alternative, depending on the drug.

HLA-B: not a breakdown gene, but an alarm gene

HLA-B is part of the immune system’s recognition system. Certain variants can cause it to respond to a drug with a severe hypersensitivity reaction. The best-known example is HLA-B*57:01 with the HIV drug abacavir. In the PREDICT-1 trial with 1,956 patients from 19 countries, testing before treatment eliminated immunologically confirmed hypersensitivity reactions: 0% in the screened group versus 2.7% in the control group (Mallal et al., New England Journal of Medicine, 2008). Today, the European public assessment report (EPAR) for abacavir calls for HLA-B*57:01 screening in all patients with HIV; carriers should not receive abacavir.

Further CPIC guidelines cover HLA-B*58:01 with allopurinol and HLA variants with carbamazepine, oxcarbazepine and phenytoin.

More genes with guidelines

The list goes on: CPIC has also published guidelines on CYP3A5 (tacrolimus), CYP2B6 (efavirenz, methadone), UGT1A1 (atazanavir), G6PD (including rasburicase and primaquine), NAT2 (hydralazine), RYR1 and CACNA1S (volatile anesthetics, succinylcholine), MT-RNR1 (aminoglycosides), CFTR (ivacaftor) and IFNL3 (peginterferon). Many of them concern specialized situations – such as transplant medicine or anesthesia.

What this means for practice

• Read the star names: variants are named according to an international nomenclature, for example CYP2D6*4. These names are maintained by the PharmVar consortium (Gaedigk et al., Clinical Pharmacology & Therapeutics, 2018).
• Check the test scope: a *1/*1 usually means that none of the tested variants was found. Which variants those are belongs in the result.
• Mind the gene–drug pair: the same result can mean the opposite for a prodrug than for an active drug.
• Look up the guideline: how a genotype becomes a recommendation is shown in Guidelines: CPIC, DPWG and drug labels; how to explain it, in Understanding and communicating results.
• Decide medically: decisions about medication – stopping, switching, changing the dose – are made by the treating physician.

Frequently asked questions

Related: What is pharmacogenetics? · Guidelines: CPIC, DPWG and drug labels · Understanding and communicating results

Note: This guide is general information for businesses and professionals and does not replace medical or legal advice. The genetic traits determined in a genetic analysis are well documented (each gene included is backed by at least three independent studies); recommendations derived from them are logical conclusions, not scientifically proven. Pharmacogenetic results do not replace a medical decision: any change to medication is made only by the treating physician. Regulations can change; errors and changes excepted.