rs2108622 — CYP4F2 V433M (*3)

Reduces vitamin K metabolism, requiring higher warfarin doses to achieve anticoagulation

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CYP4F2*3 — Vitamin K Metabolism and Warfarin Dosing

CYP4F2 encodes a cytochrome P450 enzyme11 cytochrome P450 enzyme
The CYP4F2 enzyme is the primary hepatic vitamin K1 oxidase that metabolizes vitamin K1 to hydroxyvitamin K1, effectively removing it from the vitamin K cycle. This serves as a counterbalance to VKORC1 (vitamin K epoxide reductase), preventing excessive accumulation of vitamin K. The V433M variant, also known as CYP4F2*3, is a common missense mutation that significantly impacts warfarin dosing requirements22 warfarin dosing requirements
Warfarin is an anticoagulant that works by inhibiting VKORC1, thereby limiting vitamin K availability for clotting factor activation.

The Mechanism

The rs2108622 variant causes a valine-to-methionine substitution at position 433 in the CYP4F2 protein. Research using human liver microsomes33 human liver microsomes
Tissue samples analyzed from liver banks genotyped for this variant demonstrates that individuals carrying the T allele (433Met) have both reduced CYP4F2 protein concentrations and decreased vitamin K1 oxidation activity. The T allele is associated with approximately 40-45% reduction in enzyme activity compared to the wild-type. Because less vitamin K is being metabolized and removed, hepatic vitamin K1 levels rise, providing more substrate for VKORC1 to convert into the active form needed for clotting factor synthesis. This elevated vitamin K counteracts warfarin's anticoagulant effect, necessitating higher warfarin doses to achieve the same therapeutic response.

The Evidence

The association between CYP4F2*3 and warfarin dosing was first identified in 200844 first identified in 2008
Caldwell et al. CYP4F2 genetic variant alters required warfarin dose. Blood, 2008 through a genome-wide association study that screened over 1,200 SNPs in a cohort of warfarin patients. The discovery study found that TT homozygotes required approximately 1 mg/day more warfarin than CC homozygotes across three independent cohorts representing diverse US geographic regions.

This finding has been extensively replicated worldwide55 extensively replicated worldwide
Liang et al. Influence of CYP4F2 genotype on warfarin dose requirement: a systematic review and meta-analysis. Thrombosis Research, 2012. A 2012 meta-analysis of 30 studies involving 9,470 participants confirmed that T-allele carriers require an 8.3% higher mean daily coumarin dose than CC homozygotes (95% CI: 5.6-11.1%, P < 0.0001). The effect is consistent across European and Asian populations but appears less pronounced in individuals of African ancestry, where the T allele is also much rarer.

The Clinical Pharmacogenetics Implementation Consortium (CPIC)66 Clinical Pharmacogenetics Implementation Consortium (CPIC)
Johnson et al. CPIC Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical Pharmacology & Therapeutics, 2017 incorporated CYP4F2*3 into their 2017 warfarin dosing guideline update. While the effect size is smaller than that of CYP2C9 and VKORC1 variants (which collectively explain ~40% of dose variability), CYP4F2*3 contributes an additional 1-4% to the explained variance and improves the accuracy of pharmacogenetic dosing algorithms.

Practical Implications

If you are prescribed warfarin and carry one or two copies of the T allele, you will likely need a higher maintenance dose to reach your target INR (International Normalized Ratio, typically 2-3 for most indications). CPIC recommends an optional 5-10% dose increase for non-African American individuals with at least one T allele when using a pharmacogenetic algorithm that already accounts for CYP2C9 and VKORC1 genotypes. This translates to approximately 0.5-1 mg/day additional warfarin.

The effect appears most clinically relevant in patients who also carry VKORC1 variants associated with low warfarin requirements. In these individuals, CYP4F2*3 can explain a significant portion of the remaining dose variability. The interaction makes sense mechanistically: VKORC1 variants that increase warfarin sensitivity reduce the amount of active vitamin K, while CYP4F2*3 increases available vitamin K — the two variants work in opposite directions.

It's important to note that CYP4F2 testing is considered optional rather than essential in clinical warfarin management. The major determinants remain CYP2C9 (which metabolizes warfarin itself) and VKORC1 (warfarin's direct target). However, incorporating CYP4F2*3 into dosing algorithms does incrementally improve prediction accuracy and may be particularly valuable for patients who are difficult to stabilize or who fall outside the predicted dose range from CYP2C9/VKORC1 alone.

Interactions

CYP4F2*3 is one of four genetic variants incorporated into modern pharmacogenetic warfarin dosing algorithms, alongside VKORC1 rs9923231, CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910). For individuals of African ancestry, the CYP2C cluster variant rs12777823 is more clinically relevant than CYP4F2*3.

The combined effect of these variants is complex but predictable. A person with VKORC1 AA genotype (high warfarin sensitivity) plus CYP2C9*1/*1 (normal metabolism) plus CYP4F2 TT (reduced vitamin K metabolism) represents competing influences: the VKORC1 variant lowers dose requirements substantially, while CYP4F2 TT modestly increases them. The net effect is still a lower-than-average dose, but not as low as VKORC1 AA alone would predict. Modern dosing algorithms such as those validated by the International Warfarin Pharmacogenetics Consortium77 such as those validated by the International Warfarin Pharmacogenetics Consortium
Available at www.warfarindosing.org incorporate all these variants simultaneously to generate personalized dose predictions.

Gene-gene interactions worth noting for compound implications include CYP4F2 TT + VKORC1 low-sensitivity genotypes (requiring careful upward dose titration) and CYP4F2 TT + CYP2C9 poor metabolizer status (where warfarin clearance is slow but more drug is needed to overcome elevated vitamin K). However, these interactions are generally handled by existing pharmacogenetic algorithms rather than requiring separate clinical decision-making.

Drug Interactions

warfarin dose_adjustment CPIC

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Vitamin K Metabolism Normal

Standard vitamin K metabolism and typical warfarin dose requirements

You have two copies of the common C allele, which codes for normal CYP4F2 enzyme activity. Your body metabolizes vitamin K1 at a typical rate, and this variant will not affect your warfarin dosing beyond the influence of other genetic and clinical factors. About 50% of individuals of European descent share this genotype, though the percentage varies by ancestry — it's more common in African populations (~86%) and less common in East Asian populations (~51%).

CT Reduced Vitamin K Metabolism Intermediate

Moderately reduced vitamin K metabolism requiring slightly higher warfarin doses

You have one copy of the T allele (V433M variant), which reduces CYP4F2 enzyme activity and protein concentration. This causes a modest elevation in hepatic vitamin K1 levels, meaning you will need approximately 4-8% more warfarin than CC individuals to achieve the same anticoagulant effect — typically about 0.5 mg/day higher. About 42% of people of European descent carry one copy of this variant. The effect is additive, meaning it combines with your CYP2C9 and VKORC1 genotypes to determine your overall warfarin dose requirement.

TT Significantly Reduced Vitamin K Metabolism Reduced

Substantially reduced vitamin K metabolism requiring meaningfully higher warfarin doses

You have two copies of the T allele (V433M variant), resulting in markedly reduced CYP4F2 enzyme activity — approximately 40-45% of normal levels. Your liver accumulates higher concentrations of vitamin K1 because less is being metabolized and cleared. To achieve therapeutic anticoagulation with warfarin, you will typically need 8-11% more warfarin than CC individuals, translating to approximately 0.7-1 mg/day higher doses. About 8% of people of European descent are TT homozygotes, though this is much rarer in African populations (~0.5%) and varies in Asian populations (7-9%).