Impact of CYP2C9 and VKORC1 polymorphisms on warfarin dose and anticoagulation response in cardiac valve replacement patients in Erbil, Iraq

Background and objective: Warfarin is the primary anticoagulant used in patients undergoing heart valve replacement surgery. Genetic variations in the CYP2C9 and VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1) genes have a significant impact on warfarin metabolism and sensitivity. However, there are limited studies on these variants in the Iraqi population. The purpose of this study was to assess the impact of the single-nucleotide polymorphisms (SNPs) VKORC1 -1639 G>A, CYP2C9*2, and CYP2C9*3 on anticoagulation response, time to reach therapeutic International Normalised Ratio (INR), and warfarin dosage requirements in patients undergoing heart valve replacement surgery. Methods: Fifty patients (34 Kurdish, 16 Arab) participated in a prospective observational study in Erbil, Iraq, from October 2024 to March 2025. Real-time PCR was used for genotyping. INR values, warfarin dosing, and the time in days from the first day of warfarin treatment after surgery until reaching the therapeutic INR (2–3) were recorded. Results: CYP2C9 *1/*1 was the most common genotype. VKORC1 genotype frequencies differed significantly between Kurdish and Arab patients. Warfarin maintenance dose varied significantly by CYP2C9 (p=0.017) and VKORC1 (p=0.04) genotype. Patients with CYP2C9 *2/*3 required the lowest dose (7 mg/week). CYP2C9 genotype correlated with time to therapeutic INR (p=0.043), while VKORC1 genotype did not. Conclusion: The CYP2C9 and VKORC1 polymorphisms found in the studied population require lower warfarin dosages in Iraqi patients who have undergone heart valve replacement. These results demonstrate the importance of genotype-guided warfarin dosing in enhancing safety and efficacy, especially in genetically diverse populations such as Iraq.