Friday, March 29, 2024
HomeGenomic MedicineWarfarin Dosing and VKORC1/CYP2C9

Warfarin Dosing and VKORC1/CYP2C9

Overview

Warfarin is the most commonly used vitamin K antagonist. It has demonstrated effectiveness for the primary and secondary prevention of venous thromboembolism, for the prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation, as an adjunct in the prophylaxis of systemic embolism after myocardial infarction, and for reducing the risk of recurrent myocardial infarction.

Anticoagulant therapy with warfarin is characterized by a wide interindividual variation in dose requirements and a narrow therapeutic index. Therefore, accurate dosing is critical for safely managing patients on this drug. Because nongenetic influences such as body size and age are poor predictors of an individual’s dose requirement, there has been considerable investigation into the genetic influences on warfarin dose requirements. Approximately 50% of the variability in warfarin dose requirement is attibuted to common single nucleotide polymorphisms (SNPs).

Warfarin is metabolized primarily via oxidation in the liver by CYP2C9, and it exerts its anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide polymorphisms (SNPs), 2 in the CYP2C9 gene and 1 in the VKORC1 gene, have been found to play key roles in determining the effect of warfarin therapy on coagulation.

A common reason for visits to the emergency department is complication from inappropriate warfarin dosing. It is estimated that polymorphisms in CYP2C9 and VKORC1 account for approximately 30% (20-25% for VKORC1, and 5–10% for CYP2C9) of all warfarin dose variance and are more strongly associated with warfarin stable dose than all other patient factors.

The nomenclature for the CYP2C9 SNPs is unique: the normal, or wild-type, variant is referred to as *1 (“star 1”), the 2 polymorphic versions are *2 (“star 2”) and *3 (“star 3”), and each person can carry any 2 versions of the SNP. For example, a person with 2 normal copies would be *1/*1, a person with only one polymorphism could be *1/*2, and a person with both polymorphisms could be *2/*3. The prevalence of each variant varies by race; 10% and 6% of Caucasians carry the *2 and *3 variants, respectively, but both variants are rare (< 2%) in those of African or Asian descent.

CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation.

In the VKORC1 1639 (or 3673) SNP, the common G allele is replaced by the A allele. Because people with an A allele (or the “A haplotype”) produce less VKORC1 than do those with the G allele (or the “non-A haplotype”), lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele. The prevalence of these variants also varies by race, with 37% of Caucasians and 14% of Africans carrying the A allele.

Genome-wide association studies (GWAS) have not only confirmed these observations but also identified a novel association between rs2108622 in CYP4F2 and reduced hepatic CYP4F2, higher levels of hepatic vitamin K, and higher warfarin dose requirements.

A preliminary case-control GWAS identified 4 SNPs in linkage disequilibrium on chromosome 6 (rs115112393, rs16871327, rs78132896, and rs114504854) that were associated with warfarin-related bleeding in patients of African descent. The rs16871327 and rs78132896 risk alleles together increased expression of the EPHA7 gene, which the researchers hypothesized could be the cause of warfarin-related bleeding by inhibiting ephrin receptor–ephrin interaction. However, further study is needed for verification.

RELATED ARTICLES
- Advertisment -

Most Popular