POPULATION-BASED BIOINFORMATIC CHARACTERIZATION OF VKORC1 GENE VARIANTS INFLUENCING WARFARIN SENSITIVITY-A DESCRIPTIVE STUDY

Background: Warfarin dosing varies greatly between individuals and across populations, and much of this variation is driven by polymorphisms in the VKORC1 gene. Understanding how these variants influence gene expression and function is crucial for improving dose accuracy and preventing complications. Objective: To characterise key VKORC1 variants using an in-silico approach and to assess how their predicted functional effects and population frequencies contribute to global differences in warfarin sensitivity. Methods: Genomic data from gnomAD and the 1000 Genomes Project were analysed to examine major VKORC1 variants across South Asian, European, and East Asian populations. Functional and regulatory impacts were predicted using SIFT, PolyPhen-2, PROVEAN, ConSurf, JASPAR, and RegulomeDB. Genotype frequencies were estimated using the Hardy–Weinberg model and interpreted in relation to expected warfarin dosing categories, including sensitive, intermediate, and normal-dose groups. Results: The promoter variant rs9923231 and intronic variant rs9934438, both linked to reduced VKORC1 expression and lower warfarin dose requirements, were most frequent in East Asians (around 80–90%). The 3′UTR variant rs7294, associated with higher gene activity and increased dose needs, was predominantly seen in South Asians (~69%). The rare coding variant rs61742245 (Asp36Tyr), predicted to cause major structural disruption and warfarin resistance, occurred at less than 0.1%. Overall, East Asians showed more sensitivity-linked genotypes, Europeans displayed mixed patterns, and South Asians carried more resistance-associated variants. Conclusion: VKORC1 variability significantly shapes inter-ethnic warfarin dose differences. Incorporating these variants into population-tailored dosing strategies may improve the safety and precision of anticoagulation therapy.