rs9923231 — VKORC1 -1639G>A

Warfarin sensitivity - determines initial dosing

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VKORC1 - The Warfarin Sensitivity Gene

VKORC111 Vitamin K Epoxide Reductase Complex Subunit 1 encodes the target enzyme of warfarin. While CYP2C9 determines how quickly you metabolize warfarin, VKORC1 determines how sensitive your body is to it. Together, these two genes account for about 40-50% of the variability in warfarin dose requirements between individuals, with VKORC1 alone contributing approximately 25 percent22 approximately 25 percent
Rieder MJ et al. PNAS, 2005.

The Mechanism

The -1639G>A variant33 rs9923231 is in the promoter region of VKORC1 and affects gene expression. The T allele reduces VKORC1 transcription by approximately 44% compared to the C allele44 44% compared to the C allele
measured by dual luciferase assay, producing less target enzyme. Since warfarin works by inhibiting VKORC1, having less enzyme means less warfarin is needed to achieve the same anticoagulant effect. This is why T allele carriers are "sensitive" to warfarin - they need lower doses.

Warfarin Dose Ranges

The impact on dosing is substantial: - CC genotype: typically requires 5-7mg daily - TC genotype: typically requires 3-4mg daily - TT genotype: typically requires 1.5-2.5mg daily

These are rough ranges - actual doses also depend on CYP2C9 genotype, age, weight, interacting medications, and dietary vitamin K intake.

The Pharmacogenomic Success Story

Warfarin pharmacogenomics is one of the most validated applications of personalized medicine.

Practical Implications

If you carry the T allele (AG or AA), you will need lower warfarin doses than average if ever prescribed this medication. This information should be in your medical record. While direct oral anticoagulants55 DOACs: newer blood thinners like apixaban and rivaroxaban that do not require genetic dose adjustment have replaced warfarin in many scenarios, warfarin remains the standard for mechanical heart valves and certain other conditions.

Drug Interactions

warfarin increased_toxicity CPIC
acenocoumarol increased_toxicity DPWG
phenprocoumon increased_toxicity DPWG

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Sensitivity Normal

Normal warfarin sensitivity

You have normal VKORC1 expression. About 37% of Europeans share this genotype, though the frequency varies dramatically by ancestry. Standard warfarin dosing (typically starting around 5mg) is appropriate for you.

CT Increased Sensitivity Sensitive

Increased warfarin sensitivity

You have one copy of the VKORC1 variant that reduces vitamin K cycling. About 47% of Europeans share this genotype. You'll need lower warfarin doses than average, typically around 3-4mg daily.

TT High Sensitivity Highly Sensitive

Highly sensitive to warfarin - low doses needed

You have two copies of the VKORC1 sensitivity variant. About 16% of Europeans share this genotype (much higher in East Asian populations where the TT genotype is the majority). You'll need substantially lower warfarin doses than average, often just 1-2mg daily.

Combined with CYP2C9 variants, your total dose reduction can be significant.