Warfarin pharmacogenetics: A controlled dose–response study in healthy subjects. (October 2013)

• Record Type: Journal Article
• Authors: Kadian-Dodov, Daniella L; van der Zee, Sarina A; Scott, Stuart A; Peter, Inga; Martis, Suparna; Doheny, Dana O; Rothlauf, Elizabeth B; Lubitz, Steven A; Desnick, Robert J; Halperin, Jonathan L
• Is Part Of: Vascular medicine. Volume 18:Number 5(2013)
• Page Start: 290
• Page End: 297
• Publication Date: 2013-10
• Subjects: coagulation -- CYP2C9 -- CYP4F2 -- dose–response -- healthy subjects -- pharmacogenetics -- VKORC1 -- warfarin; Blood-vessels -- Diseases -- Periodicals; Peripheral vascular diseases -- Periodicals; Vascular Diseases -- Periodicals; Vaisseaux sanguins -- Maladies -- Périodiques; Maladies vasculaires périphériques -- Périodiques; 616.13
• DOI: 10.1177/1358863X13503193
• Languages: English
• ISSNs: 1358-863X

Abstract

The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 ( p =0.004) and VKORC1 ( p =0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses ( p =0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 ( p =0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders.ClinicalTrials.gov Identifier: NCT01520402