What is CYP2C19 (Cytochrome P450 2C19) genotyping?

What is CYP2C19 Genotyping?

CYP2C19 genotyping is a genetic test that identifies specific variants (alleles) in the CYP2C19 gene to predict how an individual will metabolize certain medications, most notably clopidogrel, by determining their metabolizer phenotype (poor, intermediate, extensive, or ultrarapid metabolizer). 1

Purpose and Clinical Rationale

CYP2C19 genotyping identifies genetic variants that directly impact drug metabolism and clinical outcomes, particularly for medications requiring CYP2C19 enzyme activity for either activation (prodrugs) or inactivation (active drugs). 1

• The test screens primarily for loss-of-function (LOF) alleles (CYP2C19*2, *3, 4) and gain-of-function alleles (CYP2C1917) that alter enzyme activity. 1
• The CYP2C19 gene contains over 2000 described genetic variants, though clinical testing focuses on the most common and clinically relevant alleles. 1
• Point-of-care genotyping can provide results in less than 3 hours, making it feasible for acute clinical decision-making. 2

Key Alleles Tested

The most clinically important variants include:

• CYP2C19*1 (wild-type): Normal enzyme function 3
• CYP2C19*2: Most common LOF allele containing c.681G>A variant causing premature stop codon and non-functional protein; frequency varies by ethnicity (South Asians 32.5%, East Asians 31%, Africans 18%, Europeans 15%, Latinos 10%) 1
• CYP2C19*3: LOF allele causing premature stop codon; rare in Europeans (0.025%) and Africans (0.037%) but more common in Asian populations 1
• CYP2C19*4: LOF allele that can exist in linkage disequilibrium with *17 (designated *4B), significantly altering interpretation when testing for *17 4
• CYP2C19*17: Gain-of-function allele with increased enzyme expression and activity 1, 3

Metabolizer Phenotypes

Based on genotype results, patients are classified into four metabolizer categories:

• Poor metabolizers (PM): Two LOF alleles (*2/*2, *2/*3, *3/*3); 2-15% of population depending on ethnicity 1, 5
• Intermediate metabolizers (IM): One LOF allele and one normal allele (*1/*2, *1/*3); 18-45% of population 1
• Extensive metabolizers (EM): Two normal alleles (*1/*1) or one normal and one gain-of-function allele; represents normal metabolism 3, 5
• Ultrarapid metabolizers (UM): Carrying gain-of-function alleles (*17/*17, *1/*17); 5-30% of population 2, 6

Primary Clinical Application: Clopidogrel

The FDA has issued a black box warning encouraging CYP2C19 genotyping to guide P2Y12 inhibitor antiplatelet therapy, though routine clinical adoption remains limited. 1

Impact on Clopidogrel Metabolism

• CYP2C19 is the only CYP450 enzyme playing an important role in both steps of clopidogrel's two-step oxidative biotransformation, contributing 45% and 21% respectively to active metabolite formation. 1, 2
• Carriers of LOF alleles (*2 or *3) experience 32% reduction in active metabolite levels (AUC0-24, p<0.001) compared to wild-type subjects. 1
• Poor metabolizers have 65% reduction in clopidogrel antiplatelet efficacy and face up to 50% greater risk of thrombotic events (cardiovascular death, MI, stroke) and 3-fold increased stent thrombosis risk. 2

Clinical Outcomes Data

• In a 2025 prospective trial of 2910 acute ischemic stroke patients, carriers of CYP2C19 LOF alleles had significantly higher cardiovascular event rates (2.7% vs 1.6%, log-rank P=0.048) compared to noncarriers. 7
• Genotyping changed metabolizer classification in approximately 30% of patients when *17 testing was included, reclassifying extensive metabolizers as ultrarapid metabolizers. 4

Alternative Medications Not Affected by CYP2C19

Prasugrel and ticagrelor do not depend on CYP2C19 for their antiplatelet effects and provide consistent activity across all genetic backgrounds, making them preferred alternatives in LOF allele carriers. 1, 8

• Ticagrelor is an active compound requiring no biotransformation for reversible P2Y12 receptor inhibition. 8
• Standard dosing of ticagrelor and prasugrel applies to all patients regardless of CYP2C19 genotype. 8

Other Clinical Applications

Beyond clopidogrel, CYP2C19 genotyping has relevance for:

• Proton pump inhibitors (PPIs): Poor metabolizers experience 5-fold higher drug exposure and more effective acid suppression; genotyping may be cost-effective in Asian populations for optimizing PPI therapy duration and dosing. 5
• Phenytoin: Altered CYP2C19 activity increases plasma concentrations and toxicity risk; genotyping alongside CYP2C9 may optimize dosing given narrow therapeutic range. 5
• Tricyclic antidepressants: Increased toxicity risk in patients with diminished CYP2C19 and/or CYP2D6 activity. 5

Current Guideline Recommendations

• The 2025 UK CERSI-PGx guideline recommends CYP2C19 testing for any patient about to be prescribed clopidogrel (regardless of indication) where testing is available, and advises avoiding clopidogrel in intermediate or poor metabolizers. 9
• The American Heart Association recommends considering CYP2C19 genetic polymorphisms in patients on clopidogrel requiring surgery for perioperative antiplatelet management. 2
• The European Society of Cardiology suggests considering genotyping if available within clinical timeframe to guide perioperative management. 2

Testing Methodology

• TaqMan real-time PCR using specific primers and probes for *1, *2, *3, and *17 alleles demonstrates excellent interlaboratory concordance and is appropriate for clinical testing. 3
• Genomic DNA is extracted from EDTA whole blood samples for analysis. 3
• *Including 4B testing is essential when clinically genotyping CYP2C19, as this variant exists in linkage disequilibrium with *17 and significantly alters interpretation. 4

Important Caveats

• Nongenetic factors modulate CYP2C19 activity including enzyme inhibition (particularly omeprazole, which causes the most significant competitive inhibition), induction, advanced age, and liver cirrhosis. 2, 5
• Combining CYP2C19 with ABCB1 (P-glycoprotein) genotyping identifies approximately 1 in 3 Ashkenazi Jewish and 1 in 2 Sephardi Jewish individuals at increased risk for adverse clopidogrel responses. 4
• Ultrarapid metabolizers of clopidogrel (a prodrug) actually benefit from enhanced conversion to active metabolite, achieving superior platelet inhibition but facing higher perioperative bleeding risk. 2, 6