Warfarin pharmacogenetics: A controlled dose–response study in healthy subjects
| Autor: | Robert J. Desnick, Steven A. Lubitz, Suparna Martis, Stuart A. Scott, Sarina A van der Zee, Daniella Kadian-Dodov, Dana Doheny, Jonathan L. Halperin, Elizabeth B. Rothlauf, Inga Peter |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.medical_specialty CYP4F2 Young Adult Cytochrome P-450 Enzyme System Vitamin K Epoxide Reductases Internal medicine Humans Medicine heterocyclic compounds Cytochrome P450 Family 4 International Normalized Ratio cardiovascular diseases Dosing CYP2C9 Cytochrome P-450 CYP2C9 Dose-Response Relationship Drug business.industry Cumulative dose Confounding Warfarin Anticoagulants Genetic Variation Anesthesia Multivariate Analysis Female Aryl Hydrocarbon Hydroxylases VKORC1 Cardiology and Cardiovascular Medicine business Algorithms Pharmacogenetics medicine.drug |
| Zdroj: | Vascular Medicine. 18:290-297 |
| ISSN: | 1477-0377 1358-863X |
| DOI: | 10.1177/1358863x13503193 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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