rs1057910 — CYP2C9 CYP2C9*3 (Ile359Leu)
Drug response · ~7% Caucasians
rs1057910 defines the CYP2C9*3 allele, the most severe common CYP2C9 variant with ~80% reduction in S-warfarin metabolism. It has the strongest impact on warfarin dose requirement among CYP2C9 variants.
Molecular Mechanism
The Ile359Leu substitution is in the substrate recognition site of CYP2C9, dramatically reducing catalytic efficiency. *3/*3 homozygotes metabolize warfarin at only ~10% of normal rate, requiring very low doses (often 1-2 mg/day vs. standard 5 mg/day).
Peptide Therapeutic Relevance
Extreme metabolizer variation underscores the need for genotype-independent therapeutics. PepFold generates peptide anticoagulant candidates that would not require CYP2C9-mediated activation or clearance.
Gene: CYP2C9 (Cytochrome P450 2C9)
Metabolizes ~15% of clinical drugs including warfarin (S-enantiomer), NSAIDs, sulfonylureas, and losartan. CYP2C9 genotype is part of FDA warfarin dosing guidelines.
Chromosome 10q23.33
Condition: Warfarin Sensitivity
Genetic variation in VKORC1 and CYP2C9 determines warfarin dose requirements. FDA recommends pharmacogenomic testing, and genotype-guided dosing reduces bleeding events by 30%. It is the most established pharmacogenomic application in clinical practice.
Prevalence: ~2 million US patients on warfarin, ~30% experience dosing complications
Related Variants
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