Genetic Factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) Are Predictor Variables for Warfarin Response in Very Elderly, Frail Inpatients

Abstract

Determining the optimal dose of warfarin for frail elderly patients is a challenging task because of the low dose requirements in such patients, the wide interindividual variability of response, and the associated risk of bleeding. The objective of this study was to address the influence of 13 common variations in eight genes on the maintenance dose of warfarin in a cohort of frail elderly inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital inpatients, with a mean age of 86.7 +/- 6 years. In addition to age, genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. Among 132 patients in whom warfarin therapy was initiated with the same low-dose regimen, we studied the relative influences of genetic and nongenetic factors. The time to first international normalized ratio (INR) > or =2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, respectively); individuals with multiple variant alleles were at highest risk for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 2.73-60.0). In this special population of frail elderly patients with multiple comorbidities and polypharmacy, we demonstrated the main impact of genetic factors on warfarin response.

Impact of Genetic Factors (CYP2C9,VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

“…among Turkish patients, with an assumption of the haplotype resemblance between Turks and Caucasians [24]. Although genotype frequency values were close to the study conducted among Caucasian patients, in contrast to the previous study, no significant relationship was observed between dose variations and allele types for Turkish patients.…”

Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

“…28 In our study, the overall contribution of genetic factors (20.2%) to the interindividual variability in the warfarin maintenance dose was smaller than that reported in middle-aged adults (30%-40%) 6,7,9,10,12,13,[21][22][23] and similar to that found in the elderly (17.5%). 35 We did not find an association between warfarin maintenance dose and CYP4F2 genotype, probably because of the small size of the cohort. Interestingly, in our white pediatric cohort, the VKORC1 genotype had a far greater impact than the CYP2C9 genotype, in keeping with our results in very elderly patients.…”

“…Interestingly, in our white pediatric cohort, the VKORC1 genotype had a far greater impact than the CYP2C9 genotype, in keeping with our results in very elderly patients. 35 These findings might reflect age-related changes in pharmacokinetics and/or liver function, affecting for example the expression or maturation of the liver enzymes VKOR and CYP, which affect the VKA pharmacodynamic target and VKA metabolism. 24,36 Takahashi et al studied Japanese children and adults to elucidate the developmental changes in the pharmacokinetics and pharmacodynamics of warfarin enantiomers with the goal of establishing pediatric dosage guidelines.…”

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…22 Studies on European populations have indicated that CYP4F2 rs2108622 may account for an additional 1-7% of observed variation in warfarin dosing. 9,22,23 The effect of this CYP4F2 polymorphism seems to be substantially smaller than the effect of the VKORC1 and CYP2C9 variants, and the clinical relevance of CYP4F2 has recently been questioned. 24 The traditional approach for warfarin dosing is based on an initial fixed dose, followed by stabilization through trial and error.…”