Evaluation of the warfarin-resistance polymorphism, VKORC1 Asp36Tyr, and its effect on dosage algorithms in a genetically heterogeneous anticoagulant clinic

ObjectivesTo assess allele frequency and potential predictive value of recurrent polymorphisms affecting warfarin metabolism in an unselected patient cohort attending an anticoagulant clinic (n = 186).Design and methodsGenotyping of ten SNPs in five candidate genes (VKORC1, CYP2C9, CALU, EPHX and GGCX) was carried out by ABI PRISM SNaPshot® multiplex method.ResultsWe confirm the association between high-frequency SNPs, VKORC1 c.-1639G>A and CYP2C9 *2/*3 and warfarin sensitivity, and contribute additional evidence that the VKORC1 p.Asp36Tyr variant is recurrent and independently associated with warfarin resistance in our population. Other SNPs made little contribution.ConclusionWarfarin sensitivity was predicted by known VKORC1 and CYP2C9 SNPs. However, resistance associated with p.Asp36Tyr in VKORC1 would not be predicted by the usual markers. Despite its relatively low frequency (3/186 or 1.6%) clinical considerations may warrant its inclusion in pharmacogenetic screening for initial warfarin dosing in clinic populations with a heterogeneous population base.

► VKORC1 p.Asp36Tyr variant is associated with warfarin resistance.
► Asp36Tyr was present in 3/186 or 2% of patients in our clinic population.
► Asp36Tyr should be included in algorithms used to predict initial warfarin dosing.