Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy.

Laith Al-Eitan,Ayah Almasri,Rame Khasawneh

doi:10.3390/genes9120578

Laith Al-Eitan, Ayah Almasri + Show 1 more

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https://doi.org/10.3390/genes9120578

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Abstract

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

Highlights

Warfarin is a commonly prescribed oral anticoagulant that is employed for the treatment of venous and arterial thromboembolic disorders and cardiac valve replacements [1]
Two-thirds of warfarin dose variation was due to environmental factors like age, body mass index, smoking status, gender, and diet, among others, while the remaining one-third is caused by genetic factors such as the CYP2C9 and VKORC1 genes [4,5,6]
Belonging to the cytochrome P450 superfamily, the CYP2C9 gene is involved in the metabolism and clearance of S-warfarin, the latter of which is a racemic form of warfarin together with

Summary

Introduction

Warfarin is a commonly prescribed oral anticoagulant that is employed for the treatment of venous and arterial thromboembolic disorders and cardiac valve replacements [1]. Interindividual genetic variation causes great variability in dosage requirements, making the latter a problematic issue for physicians. Two-thirds of warfarin dose variation was due to environmental factors like age, body mass index, smoking status, gender, and diet, among others, while the remaining one-third is caused by genetic factors such as the CYP2C9 and VKORC1 genes [4,5,6]. Belonging to the cytochrome P450 superfamily, the CYP2C9 gene is involved in the metabolism and clearance of S-warfarin, the latter of which is a racemic form of warfarin together with. CYP2C9 is located on the long arm of chromosome 10, and like other members of CYP2C, CYP2C9 is highly polymorphic [9,10,11]. There are over 50 single nucleotide polymorphisms (SNPs) located in the regulatory and coding region of the CYP2C9 sequence, the most

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