Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population.

PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population. METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%). CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.

Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.

The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

Genotype-guided warfarin therapy: current status.

Warfarin pharmacogenomics has been an extensively studied field in the last decades as it is focused on personalized therapy to overcome the wide interpatient warfarin response variability and decrease the risk of side effects. In this expert review, besides briefly summarizing the current knowledge about warfarin pharmacogenetics, we also present an overview of recent studies that aimed to assess the efficacy, safety and economic issues related to genotype-based dosing algorithms used to guide warfarin therapy, including randomized and controlled clinical trials, meta-analyses and cost-effectiveness studies. To date, the findings still present disparities, mostly because of standard limitations. Thus, further studies should be encouraged to try to demonstrate the benefits of the application of warfarin pharmacogenomic dosing algorithms in clinical practice.

Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox.

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 µmol/g; reference value < 36 µmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.