CYP2C9 *3 (rs1057910) is the more severe of the two common CYP2C9 reduced-function variants, resulting in only about 5-10% of normal enzyme activity. This variant has major implications for dosing warfarin, NSAIDs, sulfonylureas, and other medications. Carriers require significant dose reductions to avoid adverse effects, making this one of the most clinically important pharmacogenetic variants.
Understanding CYP2C9 *3
The *3 variant causes more severe enzyme impairment than *2:
The Ile359Leu Change
- A allele (*1): Isoleucine at position 359 - normal activity
- C allele (*3): Leucine at position 359 - severely reduced activity (~5-10% of normal)
Understanding Your Genotype
- *1/*1 (A/A): Normal metabolizer
- *1/*3 (A/C): Intermediate metabolizer - ~65-70% reduction in activity
- *3/*3 (C/C): Poor metabolizer - ~90% reduction (rare)
Comparing *2 and *3
| Feature | *2 (rs1799853) | *3 (rs1057910) |
|---|---|---|
| Activity reduction | ~30% | ~90% |
| Allele frequency (Europeans) | ~10-15% | ~5-8% |
| Clinical impact | Moderate | Severe |
| Warfarin dose reduction | ~20% | ~40-50% |
Warfarin Dosing
Critical Importance
- *3 carriers at high risk of over-anticoagulation with standard doses
- Increased bleeding risk, including life-threatening hemorrhage
- Longer time to achieve stable INR
- Genetic testing before warfarin initiation strongly recommended
CPIC Dosing Recommendations
| CYP2C9 Status | Genotype Examples | Recommended Starting Dose |
|---|---|---|
| Normal | *1/*1 | Standard (5-7 mg/day typical) |
| Intermediate | *1/*3, *2/*2 | ~30-40% reduction |
| Poor | *3/*3, *2/*3 | ~50-70% reduction |
VKORC1 Interaction
Combined genetic effects:
- CYP2C9 *3 + VKORC1 low-dose genotype = very low dose requirement
- Some patients need only 1-2 mg daily (vs. typical 5-7 mg)
- Dosing calculators incorporate both genes
Other Critical Drug Interactions
NSAIDs
- Celecoxib: Use half the standard dose in *3 carriers
- Ibuprofen: Consider lower doses, shorter courses
- Flurbiprofen: Significantly prolonged half-life
- Risk: GI bleeding, renal effects with accumulation
Sulfonylureas
- Glipizide, glyburide, glimepiride affected
- *3 carriers at increased hypoglycemia risk
- Consider alternative diabetes medications or lower doses
- More frequent glucose monitoring recommended
Phenytoin
- Anti-epileptic with narrow therapeutic window
- *3 carriers require lower doses
- Risk of toxicity (nystagmus, ataxia, sedation)
- Therapeutic drug monitoring essential
Losartan
- Requires CYP2C9 for activation to E-3174
- *3 carriers may have reduced efficacy (paradoxically)
- Consider alternative ARBs (valsartan, irbesartan)
Direct Oral Anticoagulants (DOACs) Alternative
For anticoagulation in CYP2C9 poor metabolizers:
- DOACs (apixaban, rivaroxaban, dabigatran) less affected by CYP2C9
- May be preferable alternatives to warfarin
- No routine monitoring required
- Discuss options with healthcare provider
Drug-Gene-Drug Interactions
Compounding Effects
- CYP2C9 inhibitors (fluconazole, amiodarone) further reduce activity
- *3 carrier + strong inhibitor = essentially no CYP2C9 activity
- Extreme caution needed with CYP2C9 substrates in this situation
Clinical Vigilance
- Inform all healthcare providers of your CYP2C9 status
- Check for CYP2C9 interactions when starting new medications
- Consider pharmacist consultation for drug reviews
Population Distribution
- European ancestry: *3 allele ~5-8%
- Asian ancestry: *3 allele ~2-4%
- African ancestry: *3 very rare (<1%)
- Middle Eastern: Variable, can be higher in some populations
Testing Recommendations
Strongly Recommended Before
- Starting warfarin therapy
- High-dose NSAID therapy
- Phenytoin initiation
Consider Testing If
- Unexplained drug sensitivity
- History of adverse drug reactions
- Family history of drug sensitivities
- Starting multiple CYP2C9 substrates
Testing with NutraHacker
NutraHacker's Complete Mutation Report analyzes both CYP2C9 *2 and *3 variants along with other pharmacogenetic markers, providing comprehensive drug metabolism information.
Frequently Asked Questions
I have the *3 variant - is warfarin dangerous for me?
Warfarin isn't inherently dangerous, but standard doses would be. With appropriate dose reduction based on your genotype, warfarin can be used safely. The key is that your prescriber knows your CYP2C9 status before starting. Many *3 carriers do well on warfarin with genotype-guided dosing. Alternatively, DOACs may be considered as they're less affected by CYP2C9.
Should I avoid all NSAIDs?
Not necessarily avoid entirely, but use with extra caution. For occasional, short-term use, the clinical impact may be minimal. For regular use, consider lower doses, shorter durations, or alternative pain management. Acetaminophen (not a CYP2C9 substrate) is an option for some situations. Discuss your options with your healthcare provider.
Does this affect caffeine or alcohol metabolism?
CYP2C9 is not the primary enzyme for caffeine (CYP1A2) or alcohol (ADH, ALDH). So this variant doesn't significantly affect how you process caffeine or alcohol. However, other CYP variants analyzed in comprehensive testing may affect these substances.
References
- Johnson JA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102(3):397-404.
- Theken KN, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and NSAIDs. Clin Pharmacol Ther. 2020;108(2):191-200.
- Sullivan-Klose TH, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics. 1996;6(4):341-349.