Association of warfarin dose with genes involved in its action and metabolism

We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00439-006-0260-8 and is accessible for authorized users

Health Literacy and Anticoagulation-related Outcomes Among Patients Taking Warfarin

BACKGROUND: Little is known about whether health literacy affects anticoagulation-related outcomes. OBJECTIVE: To assess how health literacy is associated with warfarin knowledge, adherence, and warfarin control (measured by the international normalized ratio [INR]). DESIGN: Survey. PARTICIPANTS: Patients taking warfarin through an anticoagulation clinic. MEASUREMENTS: Health literacy was measured using the short-form Test of Functional Health Literacy in Adults (s-TOFHLA), dichotomized as “limited” (score 0 to 22) and “adequate” (score 23 to 36). We asked patients to answer questions relating to their warfarin therapy and used multivariable logistic regression to assess whether health literacy was associated with incorrect answers. We also assessed whether health literacy was associated with nonadherence to warfarin as well as time in therapeutic INR range. RESULTS: Bilingual research assistants administered the survey and s-TOFHLA to 179 anticoagulated English- or Spanish-speaking patients. Limited health literacy was associated with incorrect answers to questions on warfarin's mechanism (adjusted odds ratio [OR] 4.8 [1.3 to 17.6]), side-effects (OR 6.4 [2.3 to 18.0]), medication interactions (OR 2.5 [1.1 to 5.5]), and frequency of monitoring (OR 2.7 [1.1 to 6.7]), after adjusting for age, sex, race/ethnicity, education, cognitive impairment, and years on warfarin. However, limited health literacy was not significantly associated with missing warfarin doses in 3 months (OR 0.9 [0.4 to 2.0]) nor with the proportion of person-time in therapeutic INR range (OR 1.0 [0.7 to 1.4]). CONCLUSIONS: Limited health literacy is associated with deficits in warfarin-related knowledge but not with self-reported adherence to warfarin or INR control. Efforts should concentrate on investigating alternative means of educating patients on the management and potential risks of anticoagulation