rs9923231 — VKORC1 -1639G>A

Warfarin sensitivity - determines initial dosing

Established Risk Factor

Details

Gene: VKORC1
Chromosome: 16
Risk allele: A
Consequence: Regulatory
Inheritance: Codominant
Clinical: Risk Factor
Evidence: Established
Chip coverage: v3 v4 v5

Population Frequency

37%

47%

16%

Ancestry Frequencies

east_asian

89%

latino

39%

european

38%

south_asian

18%

african

10%

Related SNPs

rs1799853 (CYP2C9) rs1057910 (CYP2C9)

External

SNPedia ClinVar dbSNP

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 30%²² approximately 30%
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 A allele reduces VKORC1 transcription by approximately 44% compared to the G allele⁴⁴ 44% compared to the G 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 A allele carriers are "sensitive" to warfarin - they need lower doses.

Warfarin Dose Ranges

The impact on dosing is substantial: - GG genotype: typically requires 5-7mg daily - AG genotype: typically requires 3-4mg daily - AA 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.

Population Variation

The VKORC1 -1639A allele shows dramatic worldwide variation⁵⁵ worldwide variation
Ross KA et al. J Hum Genet, 2010: approximately 90% frequency in East Asian populations, 38% in Europeans, and only 10% in African-descent populations. This largely explains the well-known observation that East Asian patients typically need lower warfarin doses than European patients, who in turn need lower doses than African-descent patients.

The Pharmacogenomic Success Story

Warfarin pharmacogenomics is one of the most validated applications of personalized medicine. Multiple randomized controlled trials (including the landmark EU-PACT⁶⁶ EU-PACT
Pirmohamed M et al. A Randomized Trial of Genotype-Guided Dosing of Warfarin. N Engl J Med, 2013 and COAG⁷⁷ COAG
Kimmel SE et al. A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing. N Engl J Med, 2013 trials) have demonstrated that genotype-guided warfarin dosing reduces the time to stable therapeutic anticoagulation and decreases the risk of both under- and over-anticoagulation during the critical initiation period.

Practical Implications

If you carry the A 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 anticoagulants⁸⁸ 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:

GG “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.

AG “Increased Sensitivity” Sensitive Caution

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.

AA “High Sensitivity” Highly Sensitive Warning

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 AA 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.