Genetic variations in CYP2C9 and VKORC1 can significantly influence the safety and effectiveness of certain medications. Individuals carrying the CYP2C92 (rs1799853), CYP2C93 (rs1057910), or VKORC1 c.-1639G>A (rs9923231) alleles are at higher risk of adverse effects, particularly bleeding complications. Allele frequencies for CYP2C92, CYP2C93, and VKORC1 c.-1639G>A were sourced from Phase III of the 1000 Genomes Project, adhering to Fort Lauderdale data-sharing principles. Risk phenotypes were determined based on established pharmacogenomic (PGx) guidelines, classifying carriers of these variants accordingly. Approximately 17.8% (95% CI: 16.3%–19.3%) of the global population are predicted to be intermediate or poor metabolizers due to CYP2C9*2 and/or *3 variants, placing them at increased risk. This prevalence was highest in Europeans (35%; 95% CI: 30.8%–39.2%), followed by South Asians (26.8%; 95% CI: 22.9%–30.7%), Admixed Americans (25.9%; 95% CI: 21.3%–30.5%), East Asians (6.7%; 95% CI: 4.5%–8.9%), and Africans (2.1%; 95% CI: 1%–3.2%). When combining CYP2C9 and VKORC1 c.-1639G>A variants, 33.1% (95% CI: 31.3%–35%) of individuals were classified as sensitive or highly sensitive responders. This combined risk phenotype was most common in East Asians (79.6%; 95% CI: 76%–83.1%), followed by Europeans (38.6%; 95% CI: 34.3%–42.8%), Admixed Americans (30%; 95% CI: 25.2%–34.8%), South Asians (25.2%; 95% CI: 21.3%–29%), and Africans (1.2%; 95% CI: 0.4%–2%). Differences across populations were highly statistically significant (p < 0.05; χ² test, p = 1.94 × 10⁻¹⁷⁵). According to PharmGKB, at least 29 widely used drugs have their safety or efficacy affected by CYP2C9 and/or VKORC1 c.-1639G>A polymorphisms. Of these, at least 23 carry pharmacogenomic labeling information, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued dosing recommendations for at least 11 drugs based on these genetic variants. The study indicates that roughly one in five people worldwide carries CYP2C9 risk alleles that may compromise the safety of certain medications, while approximately one-third are at risk when VKORC1 variation is also considered. These findings highlight the potential value of routine pharmacogenomic testing to improve drug safety, particularly for the 11 drugs with existing CPIC guidelines. Further research is needed to assess the real-world clinical impact of implementing PGx-guided prescribing.
