rs1799853 — CYP2C9 *2

Decreased function variant affecting warfarin, phenytoin, and NSAIDs

Established Risk Factor

Details

Gene: CYP2C9
Chromosome: 10
Risk allele: T
Protein change: p.Arg144Cys
Consequence: Missense
Inheritance: Codominant
Clinical: Risk Factor
Evidence: Established
Chip coverage: v3 v4 v5

Population Frequency

80%

19%

Ancestry Frequencies

european

13%

latino

south_asian

african

east_asian

Related SNPs

rs1057910 (CYP2C9) rs9923231 (VKORC1)

External

SNPedia ClinVar dbSNP

CYP2C9*2 - The Warfarin Metabolism Gene

CYP2C9 is the primary enzyme responsible for metabolizing warfarin (Coumadin), one of the most widely prescribed and dangerous medications in clinical practice. Warfarin has an extremely narrow therapeutic window¹¹ Narrow therapeutic window: small difference between effective dose and toxic dose - too little and you risk blood clots, too much and you risk life-threatening bleeding. CYP2C9 genotype is one of the key determinants of the right dose for each individual.

The Mechanism

The CYP2C9*2 variant²² rs1799853 causes an arginine-to-cysteine substitution at position 144³³ Amino acid change: arginine to cysteine at position 144 (R144C). This amino acid change reduces the enzyme's catalytic efficiency to about 50% of normal. The enzyme is produced in normal quantities but works at roughly half speed, leading to slower clearance of warfarin and other CYP2C9 substrates. The *2 allele is most common in European populations (about 13%) and essentially absent in East Asian populations.

Warfarin Dosing Impact

Warfarin dosing is one of the most successful applications of pharmacogenomics in clinical practice. The FDA-approved warfarin label includes pharmacogenomic dosing tables based on CYP2C9 and VKORC1 genotypes. Patients with CYP2C9*2 typically need lower warfarin doses to achieve therapeutic INR levels, and they take longer to reach a stable dose. Two landmark randomized trials -- the EU-PACT trial⁴⁴ EU-PACT trial
Pirmohamed M et al. A Randomized Trial of Genotype-Guided Dosing of Warfarin. N Engl J Med, 2013 and the COAG trial⁵⁵ COAG trial
Kimmel SE et al. A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing. N Engl J Med, 2013 -- tested genotype-guided dosing in clinical practice.

Beyond Warfarin

CYP2C9 also metabolizes phenytoin (seizure medication), NSAIDs (ibuprofen, celecoxib), and several diabetes medications (glipizide, tolbutamide). Poor metabolizers may experience increased side effects from these drugs at standard doses. For NSAIDs, the CPIC guideline⁶⁶ CPIC guideline
Theken KN et al. CPIC guideline for CYP2C9 and NSAID therapy. Clin Pharmacol Ther, 2020 recommends reduced doses or alternative agents for poor metabolizers due to increased risk of gastrointestinal bleeding.

Practical Implications

If you carry the *2 allele, this is important information for any future warfarin therapy. Pharmacogenomic-guided warfarin dosing has been shown to reduce the time to stable therapeutic dosing and decrease the risk of bleeding complications. Several online dosing calculators (like warfarindosing.org⁷⁷ warfarindosing.org
Pharmacogenomic warfarin dosing calculator) incorporate CYP2C9 genotype alongside clinical factors.

Drug Interactions

warfarin increased_toxicity CPIC

phenytoin increased_toxicity CPIC

celecoxib increased_toxicity CPIC

ibuprofen increased_toxicity CPIC

flurbiprofen increased_toxicity CPIC

meloxicam increased_toxicity CPIC

piroxicam increased_toxicity CPIC

tenoxicam dose_adjustment DPWG

glipizide dose_adjustment literature

tolbutamide dose_adjustment literature

siponimod dose_adjustment FDA

losartan reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant:

CC “Normal Metabolizer” Normal

Normal CYP2C9 activity at *2 position

No reduced function variant at this position. About 80% of Europeans share this genotype. Standard dosing for CYP2C9-metabolized drugs applies.

CT “Intermediate Metabolizer” Intermediate Caution

Intermediate CYP2C9 metabolizer

You carry one copy of the CYP2C9*2 variant. About 19% of Europeans share this genotype. This affects medications like warfarin, phenytoin, and NSAIDs.

If prescribed warfarin, you may need a lower dose than average.

TT “Poor Metabolizer” Poor Warning

Poor CYP2C9 metabolizer - warfarin dose reduction needed

You are a CYP2C9 poor metabolizer at the *2 position. About 1% of Europeans share this genotype. This significantly affects warfarin dosing -- you'll need substantially lower doses.

NSAIDs may also cause more GI bleeding risk.