rs9923231 — VKORC1 -1639G>A (promoter)
Drug response · ~45% Caucasians, >90% East Asians
rs9923231 is a promoter variant in VKORC1 that reduces gene expression, making carriers more sensitive to warfarin. It is the strongest genetic predictor of warfarin dose requirement and is included in FDA-approved pharmacogenomic labeling.
Molecular Mechanism
The G>A substitution in the VKORC1 promoter reduces transcription factor binding, lowering VKORC1 mRNA and protein levels. Since warfarin directly inhibits VKORC1 (vitamin K epoxide reductase), lower baseline enzyme levels mean less drug is needed for therapeutic anticoagulation.
Peptide Therapeutic Relevance
Peptides targeting the VKORC1 enzyme complex could offer more selective anticoagulation than small-molecule warfarin. PepFold generates candidates targeting vitamin K epoxide reductase binding regions.
Gene: VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1)
Direct pharmacological target of warfarin. Recycles vitamin K, essential for gamma-carboxylation of clotting factors II, VII, IX, and X.
Chromosome 16p11.2
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
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