Mariana Rodrigues Botton

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta‐analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC‐homozygotes, T‐allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Pharmacogenomics of warfarin in populations of African descent.

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter‐ and intra‐individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub‐Saharan peoples, African Americans and admixed Brazilians. These ‘Black’ populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost‐effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio‐economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are ‘friendly’ enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity.

Risk factors for hypertensive disorders of pregnancy in southern Brazil

OBJECTIVE The aim of the study was to identify the frequency of risk factors for hypertensive disorders in pregnancy in Southern Brazil. METHODS The study included 161 patients with hypertensive disorders and 169 control subjects matched by age and ethnicity. The frequency of the risk factors was compared by Fishers exact test, chi-square and Students t test. A multivariate logistic regression analysis assessed the independent role of clinical, social and demographic factors which were associated with occurrence of the hypertensive disease in pregnancy in the univariate analysis. RESULTS Patients enrolled in the study were predominantly Caucasian (73%) and the mean age was 29. In the multivariate analysis, the variables associated were: family history of preeclampsia (p = 0.001; OR = 3.88; 95% CI = 1.77-8.46), diabetes (p = 0.021; OR = 3.87; 95% CI = 1.22-12.27) and chronic hypertension (p = 0.002; OR = 7.05; 95% CI = 1.99-24.93). CONCLUSION The risk factors associated with hypertensive disorders in pregnancy appear to be similar to those reported in other countries. The knowledge of the risk factors could be helpful in a prenatal care.

Pharmacogenetics of coumarin anticoagulants in Brazilians

Introduction: Coumarin vitamin K antagonists are the mainstay of anticoagulant therapy in atrial fibrillation, prosthetic heart valves and thromboembolic conditions. Concerns with these drugs include large inter-individual variability in dose requirements, narrow therapeutic index and need to monitor prothrombin time repeatedly. Areas covered: Pharmacogenetic studies and dosing algorithms for warfarin and phenprocoumon. Expert opinion: Gene candidate studies in Brazilian patients verified consistently the association of warfarin and pheprocoumon stable dose requirements with CYP2C9 and VKORC1 polymorphisms, and minor or no influence of other pharmacogenes (e.g., CYP4F2 and F7). The predictive power of warfarin and phenprocoumon dosing algorithms developed for Brazilians compares favorably with those reported for other populations. A warfarin dosing algorithm derived for an admixed cohort performed equally well in self-reported White and Black patients, in marked contrast with the considerably poorer performance of other warfarin algorithms in patients of African descent compared to those of European ancestry. This discrepancy is ascribed to the extensive European/African admixture among Brazilians. Prospective studies of clinical utility of coumarin dosing algorithms, in the context of the Brazilian Public Health System, would represent an important counterpart to recently published trials in European and North American cohorts with predominant or exclusive European ancestry.

A New Algorithm for Weekly Phenprocoumon Dose Variation in a Southern Brazilian Population: Role for CYP2C9, CYP3A4/5 and VKORC1 Genes Polymorphisms

Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non‐genetic factors. Phenprocoumon metabolism is mediated by CYP2C9 and CYP3A enzymes. Moreover, VKORC1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP3A4 and CYP3A5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of European ancestry, were investigated. Genotypes were determined by allelic discrimination with TaqMan assays. Polymorphisms −1639G>A and 1173C>T in VKORC1 and the presence of CYP2C9*2 and/or CYP2C9*3 are associated with lower doses. On the other hand, 3730G>A in VKORC1 gene is associated with higher doses. No association was found between CYP3A4*1B, CYP3A5*3 and CYP3A5*6 polymorphisms. Among non‐genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and β‐blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm.

Immune system polymorphisms and factor VIII inhibitor formation in Brazilian haemophilia A severe patients

patients who have the potential of osteochondral remodelling [5], however, it is not popular for the elbow because of technical difficulty; the joint cavity is small and close to the major neurovascular structures. But technical development enabled arthroscopic elbow surgery possible and popular [6]. In medication, development of bypassing agents, such as activated prothrombin complex concentrate (aPCC), and activated recombinant factor VII (rFVIIa) made it possible to apply surgery for an inhibitor patient of haemophilia [7,8]. Our patient was a juvenile with high responded inhibitor and just lost his elbow function because of early or moderate stage of haemophilic arthropathy. Arthroscopic elbow synovectomy w/o radial head shaving was successfully performed by covering with rFVIIa, which resulted in not only good control of articular bleeding but also functional improvement. Radiographic improvements in his left elbow suggest the effectiveness of this approach, especially for young less-progressive haemophilic arthropathy. Even in more degenerative right elbow, functional improvement was achieved after shaving of the radial head. In the past, arthroscopy was not popular for the elbow because the joint cavity is small and close to major neurovascular structures. Technical developments have recently enabled more successful arthroscopies of the elbow. Haemophilic arthropathy may be improved especially in young patients with the potential of osteochondral remodelling. Use of rVIIa enabled us to perform two such procedures in a patient with an inhibitor to factor IX.

Influence of the CYP2C9*3 allele on the pharmacological interaction between warfarin and simvastatin

A letter in response to: Andersson ML, Eliasson E, Lindh JD. A clinically significant interaction between warfarin and simvastatin is unique to carriers of the CYP2C9*3 allele. Pharmacogenomics 13(7), 757-762 (2012).

PPARA gene and phenprocoumon: a new predictor of response variability.

Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor-α) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results.

Factor VIII mutations and inhibitor formation in a southern Brazilian population.

A total of 110 patients with severe (n = 43), moderate (n = 15) or mild (n = 52) haemophilia A were studied in relation to their F8 gene mutation and inhibitor status. Nineteen percentage of them had anti-factor VIII antibodies. Significant heterogeneity in inhibitor prevalence considering the location of the patients’ mutation was found, with higher frequencies in carriers of mutations in the C1 and B domains. Twelve specific mutations showed associations with inhibitor formation, seven deletions, two nonsense, two insertions and one missense changes. Bioinformatic analysis of the missense mutation confirmed the formation of a B-cell epitope in the protein. This information is important for comparative purposes with series of other ethnic constitutions, as well as for individual prevention of this serious clinical problem in the patient population.