Pharmacogenomics

DPYDFluoropyrimidine toxicity

DPYD encodes the enzyme that breaks down fluoropyrimidine chemotherapy (5-FU, capecitabine). Reduced activity lets the drug accumulate to toxic levels — occasionally fatally.

• capecitabineCPIC A
• fluorouracilCPIC A
• tegafur

Calls the four CPIC-tier variants, including the HapB3 haplotype; rarer no-function alleles are not assessed.

TPMTThiopurine methylation

TPMT methylates thiopurine drugs into inactive metabolites. Low activity diverts the drug toward bone marrow, where it can cause severe, sometimes life-threatening myelosuppression.

• azathioprineCPIC A
• mercaptopurineCPIC A
• thioguanineCPIC A

Calls *2, *3B and *3C, which together account for most TPMT deficiency. *3B and *3C carried together are assumed to be *3A in cis (the CPIC convention for unphased data); rarer alleles are not assessed and enzyme-activity testing remains the clinical standard.

NUDT15Thiopurine tolerance

NUDT15 inactivates thiopurine metabolites. Reduced activity allows them to build up in bone marrow, raising the risk of severe myelosuppression.

• azathioprineCPIC A
• mercaptopurineCPIC A
• thioguanineCPIC A

NUDT15*3 is the most common reduced-function allele (notably in East Asian and Hispanic populations); rarer alleles are not assessed.

CYP3A5Tacrolimus clearance

CYP3A5 clears the transplant immunosuppressant tacrolimus. Most people carry two copies of the non-functional *3 allele and clear the drug slowly; people who express the enzyme clear it fast and reach lower blood levels on a standard dose.

• tacrolimusCPIC A
• atorvastatin
• cyclosporine
• fluvastatin
• lovastatin
• pitavastatin
• pravastatin
• rosuvastatin
• simvastatin
• sirolimus
• midazolam

Calls *3, *6 and *7. *3 is the common allele in most populations, so most people of European ancestry are non-expressers; *6 and *7 matter mainly in African-ancestry populations. Rarer alleles are not assessed.

SLCO1B1Statin myopathy risk

SLCO1B1 transports statins into the liver. Reduced-function alleles raise blood statin levels and the risk of muscle side effects — most pronounced with simvastatin, but CPIC also gives guidance for atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin and rosuvastatin.

• atorvastatinCPIC A
• fluvastatinCPIC A
• lovastatinCPIC A
• pitavastatinCPIC A
• pravastatinCPIC A
• rosuvastatinCPIC A
• simvastatinCPIC A
• elagolix
• methotrexate

ABCG2Rosuvastatin exposure

ABCG2 pumps rosuvastatin out of cells and into bile. The Q141K variant weakens that transport, raising blood levels of the drug — and it also tracks with a weaker response to allopurinol.

• rosuvastatinCPIC A

CYP2C9Warfarin & NSAID metabolism

CYP2C9 clears warfarin, phenytoin, and many NSAIDs — including celecoxib, ibuprofen, meloxicam and piroxicam. Reduced-function alleles slow that clearance, lowering the warfarin dose you need and raising exposure to the others.

• celecoxibCPIC A
• flurbiprofenCPIC A
• fluvastatinCPIC A
• fosphenytoinCPIC A
• ibuprofenCPIC A
• lornoxicamCPIC A
• meloxicamCPIC A
• phenytoinCPIC A
• piroxicamCPIC A
• siponimodCPIC A
• tenoxicamCPIC A
• warfarinCPIC A
• acenocoumarolCPIC B
• avatrombopag
• dronabinol
• erdafitinib
• lesinurad
• aceclofenac
• aspirin
• diclofenac
• flibanserin
• indomethacin
• lumiracoxib
• nabumetone
• naproxen

Calls *2 and *3 plus the *5, *6, *8 and *11 alleles that matter most in African-ancestry populations. The CYP2C-cluster variant rs12777823, which also informs warfarin dosing in that group, is not assessed here.

VKORC1Warfarin sensitivity

VKORC1 is the direct target of warfarin. The -1639A promoter allele lowers VKORC1 expression, so less warfarin is needed to achieve the same effect.

• warfarinCPIC A

CYP4F2Warfarin dose requirement

CYP4F2 removes vitamin K from circulation. The *3 allele leaves more vitamin K available, so carriers typically need a slightly higher warfarin dose to reach the same effect.

• warfarinCPIC A
• acenocoumarolCPIC B
• phenprocoumonCPIC B

CYP2C19Antidepressant, stomach-acid & clopidogrel response

CYP2C19 clears several common antidepressants (citalopram, escitalopram, sertraline and some tricyclics), the proton-pump inhibitors used for reflux and ulcers, and the antifungal voriconazole — and it activates the antiplatelet clopidogrel into its working form. Activity ranges from poor to ultrarapid depending on which alleles you carry.

• amitriptylineCPIC A
• citalopramCPIC A
• clopidogrelCPIC A
• escitalopramCPIC A
• lansoprazoleCPIC A
• omeprazoleCPIC A
• pantoprazoleCPIC A
• sertralineCPIC A
• voriconazoleCPIC A
• brivaracetamCPIC B
• clomipramineCPIC B
• dexlansoprazoleCPIC B
• doxepinCPIC B
• imipramineCPIC B
• trimipramineCPIC B
• carisoprodol
• clobazam
• diazepam
• duloxetine
• esomeprazole
• flibanserin
• fluoxetine
• fluvoxamine
• paroxetine
• rabeprazole
• venlafaxine
• vortioxetine

Calls the common *2, *3, *4 and *17 alleles. CYP2C19 lacks the copy-number complexity of CYP2D6, so common-allele calling is well supported — but rare alleles are not assessed.

UGT1A1Irinotecan, atazanavir & bilirubin handling

UGT1A1 glucuronidates bilirubin, the active metabolite of irinotecan, and is inhibited by the HIV drug atazanavir. Reduced activity (the *28 allele, behind Gilbert syndrome, and *6) raises the risk of irinotecan toxicity and of atazanavir-related jaundice.

• atazanavirCPIC A
• irinotecanCPIC A
• belinostatCPIC B
• dolutegravir
• nilotinib
• pazopanib
• raltegravir

Calls the *6 coding variant, common in East Asian populations. The *28 TA-repeat behind Gilbert syndrome cannot be read from single-variant data and is listed under deep analysis; rarer alleles are not assessed.

NAT2Acetylator status

NAT2 acetylates a family of older drugs. Roughly half of people of European ancestry are slow acetylators, which raises exposure — and with it the chance of isoniazid liver injury or hydralazine-induced lupus.

• hydralazineCPIC A
• amifampridine
• amifampridine phosphate
• procainamide
• sulfamethoxazole / trimethoprim
• sulfasalazine
• isoniazid

Calls the three slow-defining alleles *5, *6 and *7 against the rapid *4, without phasing — the standard approach for unphased data, and accurate for most people, but rarer NAT2 haplotypes are not assessed.

CYP2B6Efavirenz metabolism

CYP2B6 clears the HIV drug efavirenz. Reduced-function alleles raise blood levels, which is the main driver of the vivid dreams, dizziness and other central nervous system effects that lead people to stop the drug.

• efavirenzCPIC A
• sertralineCPIC B
• bupropion
• nevirapine
• methadone

Calls *6 (516G>T with 785A>G), *9 (516G>T alone) and *18. Unphased, a 516G>T and 785A>G carried together are read as one *6 chromosome; rarer alleles are not assessed.

CFTRIvacaftor response

CFTR encodes the chloride channel that is faulty in cystic fibrosis. Ivacaftor helps some faulty channels open, so it works only for people whose CF involves specific responsive variants.

• ivacaftorCPIC A
• ataluren

Calls the ivacaftor-responsive variants from CPIC's guideline; the much longer list of variants now approved for ivacaftor and combination modulators (such as elexacaftor/tezacaftor/ivacaftor) is not assessed.