Dec 01, 2023
'Warfarin', a coumarin anticoagulant, is widely used in the prevention and treatment of various thromboembolic diseases such as atrial heart valve replacement, deep vein thrombosis, pulmonary embolism and fibrillation (Wattanachai et al., 2017; Li et al. 2022). For over 50 years, coumarin drugs have been the only oral anticoagulants used by clinicians (Mega & Simon, 2015). Various disadvantages and complications in warfarin treatment, such as venous blood collection, risk of bleeding and thrombotic events, are troublesome factors for patients (Li et al. 2022). It has been reported that warfarin dose requirements are related to various genetic and non-genetic factors such as body mass index and age (Bourgeois et al. 2016). For these reasons and because genetic polymorphisms play a role in the pharmacological effect of warfarin, the dose of warfarin should be personalized (Wattanachai et al., 2017). One of the genes identified as responsible for warfarin treatment, which is also known to interfere with vitamin K metabolism (Guimarães et al., 2019), is vitamin K epoxide reductase complex subunit 1 (VKORC1) (Wattanachai et al., 2017). The VKORC1 enzyme, which is the target enzyme of warfarin action, is encoded by the VKORC1 gene. Warfarin shows its anticoagulant effect by inhibiting VKORC1. SNPs in VKORC1 affect transcription and may alter the pharmacological effects of warfarin. VKORC1 rs9923231 G > A(promotor), rs9934438 C > T(in introns) are the most common SNPs. Both SNPs are associated with reduced warfarin dose. VKORC1 rs9923231 G>A promoter polymorphism is associated with decreased VKORC1 mRNA expression and requires lower warfarin dosage. Studies have reported that those carrying single or double variants of VKORC1 rs9923231,rs9934438 SNPs require lower warfarin doses than the wild type (Wadelius et al., 2005; Rieder et al., 2005; Miao et al., 2007; Lee et al., 2009; Sangviroon et al., 2010).
Warfarin is recommended for life after artificial valve replacement. A study was conducted to adjust the warfarin drug dose in 476 patients between the ages of 18-70 who underwent artificial valve replacement in China. It was determined that it was 5.025± 0.413 mg in the GG group. As can be seen, the warfarin dose requirement of AA and AG groups is lower than those with GG genotypes. VKORC1 rs9934438 (1173C > T), daily warfarin dose in the TT genotype group was found to be 2.475 ± 0.557 mg, CT 3.109 ± 0.844 mg and CC 4.015 ± 1.581 mg, and it was stated that the alleles with the variant had a lower warfarin requirement than the wild type (Li et al. 2022). In another study conducted on Thai patients, genetic factors in warfarin dose changes were examined and VKORC1 - 1639G > A rs9923231 and polymorphism were examined. It was determined that patients with GA and AA genotypes required a lower dose of warfarin than patients with wild type GG genotype. It has been stated that AA genotype should take 18.1 mg less warfarin and GA genotype should take 9.7 mg less warfarin than GG genotype (Wattanachai et al., 2017). It has been stated that mRNA expression is decreased due to the polymorphism in approximately 90% of Asians carrying the A allele of VKORC1, which explains the low dose of warfarin. It has been stated that VKORC1 (1639G>A), AA homozygous genotype and GA heterozygous genotype require lower doses of warfarin compared to the wild type. When VKORC1 SNP carries the A allele, there was less VKORC1 expression compared to those carrying the G, therefore it was determined that a lower dose of warfarin was required to obtain anticoagulant effect. The homozygous AA allele had less VKORC1 enzyme and lower vitamin K, and was observed to cause less clotting (Shafique et al., 2021). As a result, when considering treatment with warfarin, analyzing genetic variations is very important in determining the dose.
REFERENCES
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