Limitations of VKORC1 rs9934438 as a Surrogate Marker for Vitamin K Antagonist Dose Adjustment

VKORC1 genetic variants are major determinants of interindividual variability in vitamin K antagonist (VKA) dose requirements and are incorporated into several pharmacogenetic dosing guidelines. The promoter variant rs9923231 is considered the clinically relevant marker for genotype-guided VKA dosing. However, the intronic variant rs9934438 is sometimes used as a surrogate marker because it is assumed to be in strong linkage disequilibrium with rs9923231. We aimed to assess whether rs9934438 can reliably substitute rs9923231 in clinical practice. We conducted a retrospective, single-centre study including 939 patients who underwent pharmacogenetic testing. Both variants were genotyped using a TaqMan OpenArray custom panel. Concordance between rs9934438 and rs9923231 was evaluated, and the diagnostic performance of rs9934438 for predicting clinically relevant rs9923231 diplotypes was assessed. Although concordance was high overall, rs9934438 misclassified two patients who, according to rs9923231, required a reduced VKA dose, resulting in potential false-negative classifications. These findings indicate that, while rs9934438 provides informative results in most cases, it may fail to identify some patients requiring dose adjustment. Our results highlight the clinical implications of relying on surrogate markers in pharmacogenetic-guided VKA therapy and support the preferential use of rs9923231 to ensure accurate individualized dosing and optimize treatment safety.