Auswahl der wissenschaftlichen Literatur zum Thema „Vkorc1 gene“

Warfarin is an oral anticoagulant used to prevent or treat clotting disorders associated with venous thrombosis, pulmonary embolism, atrial fibrilation, cardiac valve replacement, stroke and acute myocardial infarction. It is a vitamin K antagonist composed of S- and R- isomers. The more potent S-warfarin is metabolized by cytochrome 450 isoenzyme 2C9 (CYP2C9), encoded by CYP2C9 gene. Warfarin exerts its anticoagulants effect by inhibitingits target enzyme vitamin K epoxide reductase (VKOR), encoded by vitamin K epoxide reductase subunit 1 (VKOR1) gene. Genetic variation in the CYP2C9 and VKOR1 gene can affect warfarin efficacy and dose required to achieve stable International Normalization Ratio (INR). Specifically two variants in the CYP2CP gene (CYP2C9*2 and CYP2C9*3) result in an enzyme with reduced activity, leading to increased active warfarin levels. A variant in the VKORC1 gene (VKORC1-1639 G>A) can lead to reduced gene expression resulting in decresed level of VKOR. Together these three variants can account for 40-70% of the variability of warfarin dose. Carriers of variant alleles are at higher risk for bleeding complications, particularly at the induction of warfarin therapy. So, genotype-guided dosing algorithms would be better approximate for maintenance of warfarin dose than fixed-dose algorithms. University Heart Journal Vol. 15, No. 2, Jul 2019; 74-78

SummarySince the discovery of vitamin K epoxide reductase complex subunit 1 (VKORC1), the key enzyme for the regeneration of vitamin KH2, numerous studies have addressed the role of VKORC1 in the posttranslational modification of vitamin K-dependent proteins. VKORC1 is also the target protein of anticoagulant drugs of the coumarin type (e.g. warfarin). Genetic variants in VKORC1 have recently been shown to significantly affect the coumarin dose and international normalised ratio level. In the present study, we have used the split-ubiquitin yeast two-hybrid system to identify potential interaction partners of VKORC1. With this system we could identify 90 candidates. Out of these, we focused on VKORC1 itself, its paralog VKORC1L1, emopamil binding protein (EBP) and stress-associated endoplasmic reticulum protein 1 (SERP1). By coimmunprecipitation and colocalisation experiments, we were able to demonstrate evidence for the interaction of these proteins. Mutations in the EBP gene cause X-linked dominant chondrodysplasia punctata (CDPX2) which can be considered as a phenocopy of warfarin embryo-pathy. The interaction could be a link between these phenotypes. SERP1 represents an oxidative stress-associated endoplasmatic reticulum protein with chaperon-like functions. Antioxidant capacities have been described for vitamin K hydroquinone, the substrate of VKORC1. Both VKORC1 and SERP1, might have a synergistic function in eliminating reactive oxygen species generated during the VKOR redox process. Further studies are needed to investigate the role of these proteins in the vitamin K pathway.

A warfarin és az acenokumarolok a leggyakrabban alkalmazott antikoagulánsok, amelyek szűk terápiás tartománnyal rendelkeznek, a hatásos dózis pedig populáción belül és egyénenként is nagy változatosságot mutat. A kumarinok a K-vitamin-epoxidreduktáz enzim (VKOR) gátlásán keresztül akadályozzák meg a koagulációt. Az enzimet kódoló VKORC1 gén mutációi jelentősen befolyásolják a kumarinok iránti érzékenységet. A VKORC1 gén genetikai variabilitását a *2, *3 és a *4 haplotípusok fedik le a kaukázusi populációban. Antikoaguláns kezelésben részesülő betegek bemutatásán keresztül összefoglaló tanulmányban ismertetjük a VKORC1 gén haplotípusának variabilitását. Munkánkban 28, klinikailag nem szokványos antikoaguláns választ produkáló beteget karakterizáltunk a VKORC1 G-1639A, G9041A és C6009T polimorfizmusokra. Molekuláris módszerként PCR-RFLP technikát és direkt szekvenálást alkalmaztunk. Betegpopulációnkban sikerült kimutatni VKORC1 *1*2, *2*2, *2*3, *1*4, *2*4 és *3*4 haplotípusokat. Vizsgált betegeink körében előfordult a VKORC1 gén haplotípusa alapján közepes dózisigényű (4,9±0,2 mg/nap) A/B haplocsoportú (a vizsgált betegek 61%-a) és magas dózisigényű (6,2±0,3 mg/nap) B haplocsoportú (25%) beteg is. Az antikoaguláns terápia vérzéses szövődményeinek megelőzésében fontos az alacsony warfarindózisú (2,7±0,2 mg/nap) A haplocsoportba tartozó betegek (esetünkben 14%) diagnosztizálása. Eredményeink mutatják, hogy a haplocsoport-vizsgálat segíti a megfelelő szintű véralvadásgátláshoz szükséges gyógyszerdózis meghatározását és a végzetes vérzési epizódok elkerülését.

Abstract Purpuse: Coumarins are known for their high inter-individual and inter-ethnical variability of the dose-response association (i.e. significant higher maintenance dose in Africans and lower dose in Chinese). Recently, common SNPs of the VKORC1 gene (encoding the molecular target of coumarins, vitamin K epoxide reductase) were shown to be associated with lower warfarin dose requirement (c.-1639G>A [rs17878363], c.173+1000C>T [rs9934438]). In order to clarify whether these SNPs are part of more extended haplotypes, we established a comprehensive haplotype map of the entire VKORC1 gene locus. The association of VKORC1-haplotypes with coumarin dose requirement was analysed in different ethnical populations and patient cohorts. Methods: In 200 German blood donors the VKORC1 gene locus was analysed by direct sequencing. VKORC1 genotype data in 7 additional populations from Africa, Asia and Europe were retrieved from internet databases. Haplotype frequencies were inferred using EHplus and FAMHAP. Unselected patients receiving phenprocoumon (n=61) and patient cohorts of European origin with either increased coumarin sensitivity (n=14, weekly phenprocoumon dose <6mg) or partial coumarin resistance (n=36, weekly phenprocoumon dose >42 mg or warfarin dose>70mg) were typed for VKORC1 haplotypes. Results: In 200 controls we identified 28 SNPs within the VKORC1 gene. 6 SNPs formed 3 main haplotypes covering more than 99% of the genetic variability of VKORC1 (VKORC1*2: 42%, VKORC1*3: 38%, and VKORC1*4: 20%). SNPs associated with low warfarin dose (rs17878363, rs9934438) were in complete linkage disequilibrium with the VKORC1*2 haplotype. Haplotype frequency in Africans and Chinese differed significantly from the European sample (for VKORC1*2: Europeans 42%, Chinese 95%, Africans 14%). In 61 unselected patients receiving phenprocoumon c.-1639AA genotype patients (homozygous VKORC1*2) required less phenprocoumon (1.40 mg/d) than AG (2.12 mg/d) and GG patients (3.02 mg/d).13 of 14 patients (93%) with increased coumarin sensitivity but none of the patients with partial coumarin resistance were c.-1639AA. Vice versa, the c.-1639G allele (present in the non VKORC1*2 haplotypes) was found homozygous in 31 patients (86%) with partial coumarin resistance but in none of the patients with increased coumarin sensitivity. Conclusions: Three main haplotypes represent more than 99% of VKORC1’s genetic variability in Europeans. VKORC1 haplotypes are strongly associated with the inter-individual and inter-ethnical variability of oral anticoagulation. In future studies, VKORC1-haplotype testing may provide a clinically relevant predictor of coumarin dosing and bleeding risk in oral anticoagulation.

Abstract Coumarins target blood coagulation via inhibition of the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, an essential cofactor for the post-translational gamma-carboxylation of several blood coagulation factors. Recently, two groups including ours identified a key component of the VKOR which we named Vitamin K Epoxid Reductase Subunit 1 (VKORC1). The corresponding gene comprises a 5 kb genomic region and consist of three exons encoding a small 163 aa transmembrane protein. Since VKOR was hypothesized to be involved in two heritable diseases, combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) and resistance to coumarin-type drugs (warfarin/phenprocoumon resistance, WR) we sequenced the VKORC1 gene in patients with these phenotypes. The same homozygous missense mutation (R98W) was found in two families from Germany and Lebanon with a mild VKCFD2 phenotype. In 7 patients from 5 families with various degrees of WR (weekly warfarin dose ranged from 115 mg to 280 mg, two patients exhibited complete WR) different heterozygous missense mutations distributed throughout the gene (V29L, V45A, R58G, V66M, L128R) were identified. Furthermore, we proved a heterozygous nonsense mutation (W5Stop) in a young female patient with highly increased phenprocoumon sensitivity. Over-expression of the wild-type protein in HEK 293 cells leads to a striking increase in VKOR activity which is sensitive to warfarin inhibition. In contrast to the wild-type protein, the VKCFD2 variant exhibited a dramatically decrease of VKOR activity. The WR variants showed a varying reduction of the VKOR activity, but unexpectedly, were sensitive to warfarin in the HEK cell expression system The reason for the differing WR phenotypes in human and in the HEK cell expression system are still to be elucidated. In conclusion, VKORC1 protein most likely represents the molecular target of coumarins, which have prescribed for oral anticoagulant therapy since more than 60 years. Mutations in the VKORC1 gene are causative for the hereditary conditions of VKCFD2, warfarin resistance and also warfarin sensitivity. Our findings may provide a basis for a rational design of novel anticoagulants targeting VKOR in the future.

Background: Distribution of CYP2C9 and VKORC1 gene polymorphisms may vary significantly among different ethnic groups, and eventually influence the variation in drug metabolism or even failure.Objective: The aim of this study was to evaluate the prevalence of CYP2C9 and VKORC1 alleles in the healthy population of Republic of Macedonia compared to the global geographic data reported from different ethnic populations. Also, to genotype CYP2C9 and VKORC1 genes and eventually to divide individuals in poor, extensive, or intermediate metabolizer.Material and Methods: Blood samples were collected after signing written consent, DNA was isolated from peripheral blood, and CYP2C9 and VKORC1 genes were typed (n=124). Genotyping was performed by commercially available kits (GeneID GmbH, Strassberg, Germany, AID Diagnostica), based on the method of polymerase chain reaction with a subsequent hybridization. The population genetics analysis package, PyPop ver. 0.6.0, was used for analysis of the data.Results: The frequency of alleles varies from 0.931 for CYP2C9*3 to 0.109 for CYP2C9*2 indicating common “wild type” allele in those genes. The frequency ranges spanned ~50% for each allele of VKORC1 gene, indicating no common “wild type” allele in this gene. Test of neutrality showed significant negative value for VKORC1 polymorphism that indicates balancing selection operating on the alleles at that locus. All polymorphisms of CYP2C9*2, CYP2C9*3 and VKORC1 showed a good fit with Hardy-Weinberg expectations.Conclusion: The results of polymorphic alleles of CYP2C9 and VKORC1 genes in Macedonian population can be used for the variation in drug metabolism studies as well for adapting dosage regimes for oral anticoagulant therapies.

SummaryRecently, the C-allele of polymorphism rs2359612 (VKORC1: c.283+837C>T) in the VKORC1 gene has been reported to represent a major risk factor for coronary heart disease (CHD), stroke, and aortic dissection in Chinese patients. VKOR activity itself is the rate-limiting step in gamma-carboxylation of vitamin K-dependent coagulation factors (factors II, VII, IX, X, protein C, S, and Z) and proteins of calcium metabolism (matrix Gla protein and osteocalcin). Gamma-carboxylation is essential for the biological activity of these proteins that have been previously hypothesised to play a role in the pathogenesis of atherosclerosis. It was the objective of this study to analyse the VKORC1 genotype frequency in patients with CHD and controls from Northern Germany and to investigate the association of VKORC1 and CHD risk in patients with an European background. CHD paients (n = 901) and healthy controls (n = 521) were part of the PopGen biobank. Case and control samples were matched for ethnic and geographic origin, age and gender. After typing German CHD patients and control individuals, no evidence for a statistically significant association was detected between VKORC1 genotype and CHD phenotype. Also stratification for gender and myocardial infarction yielded no significant results. In conclusion, the discrepant association findings in Chinese and German populations may be explained by ethnic differences in genetic and perhaps environmental predisposition, modifying the polygenic CHD phenotype by interacting withVKORC1 variants and thus conferring disease susceptibility in some populations, but not in others.

Osteocalcin (OCN) is an osteoblast-derived hormone favoring glucose homeostasis, energy expenditure, male fertility, brain development, and cognition. Before being secreted by osteoblasts in the bone extracellular matrix, OCN is γ-carboxylated by the γ-carboxylase (GGCX) on three glutamic acid residues, a cellular process requiring reduction of vitamin K (VK) by a second enzyme, a reductase called VKORC1. Although circumstantial evidence suggests that γ-carboxylation may inhibit OCN endocrine functions, genetic evidence that it is the case is still lacking. Here we show using cell-specific gene inactivation models that γ-carboxylation of OCN by GGCX inhibits its endocrine function. We further show that VKORC1 is required for OCN γ-carboxylation in osteoblasts, whereas its paralogue, VKORC1L1, is dispensable for this function and cannot compensate for the absence of VKORC1 in osteoblasts. This study genetically and biochemically delineates the functions of the enzymes required for OCN modification and demonstrates that it is the uncarboxylated form of OCN that acts as a hormone.

SummaryThe gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship betweenVKORC1 and warfarin dose response, we studied theVKORC1 gene (VKORC1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation.Three of these had serum warfarin concentrations within the therapeutic range of 0.7–2.3 mg/l and showed wild-type VKORC1 sequence. The fourth warfarin resistant individual had consistently high ( ≥ 5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC1 showed a heterozygous 196G→ A transition that predicted aVal66Met substitution in the VKORC1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin.These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K 1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution.The association between a nucleotide transition in VKORC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarin and indicates that VKORC1 sequence is an important determinant of the warfarin dose response.

Background. The role of the VKORC1 (1639GA, rs9923231) gene polymorphism in hypersensitivity to warfarin and hypocoagulation is known. It has been proven that polymorphisms in the VKORC1 gene can lead to the progression of atherosclerosis and hypercoagulability, and, therefore, can be factors contributing to the development of acute coronary syndrome. Aim. To study the effect of polymorphic genotypes carriage of the VKORC1 gene on the clinical and laboratory parameters of patients with acute coronary syndrome. Material and methods. The pilot observational cross-sectional study involved 77 patients who were under observation in the conditions of the Federal Center for Cardiovascular Surgery in Astrakhan and the vascular center of Kirov City Hospital No. 3 (Astrakhan), from October 2020 to May 2021. Genotyping for CYP2C9, VKORC1, CYP4F2 on a PCR analyzer was performed. For statistical processing, the HardyWeinberg and Student criteria; 95% confidence interval were determined using Statistica Trial 13 and IBM SPSS Statistics 26.0. Differences were considered statistically significant at p 0.05. Results. Significant differences related to the frequency of hemodynamically significant stenosis in homozygous carriers of the GG gene for VKORC1 compared with the group of carriers of the GA genotype 3 (8.8%) versus 7 (22.5%); p=0.0058. Carriers of the GA and GG genotypes were most often diagnosed with myocardial infarction (Q- and non-Q-forming). Carriers of the AA genotype were more likely to have new or progressive angina pectoris. The level of hyperglycemia and triglyceridemia was the highest in the group of patients with the AA genotype, VKORC1 gene. Conclusion. Statistically significant differences were established in the clinical and laboratory parameters of patients with acute coronary syndrome, carriers of different genotypes of the VKORC1 gene.

Annually Stroke affects 16 million people and causes the death of nearly 6 million. 88% of all strokes account for ischemic stroke genesis. Disorders in processes of hemostasis and ectopic calcification play the important role in ischemic atherothrombotic stroke development. Today distinguished the group of vitamin K-dependent proteins that includes proteins, which provide hemostasis and proteins that have anticalcifications properties.

A varfarina é o anticoagulante oral mais prescrito no mundo todo. Algoritmos farmacogenéticos têm sido desenvolvidos para estimar a dose de varfarina. Os principais objetivos deste estudo foram desenvolver um algoritmo farmacogenético estimador de dose de varfarina e comparar o algoritmo desenvolvido neste trabalho com algoritmos disponíveis na literatura. Para atingir os objetivos foram incluídos dois grupos de pacientes tratados com varfarina (primeira coorte, n = 832; e segunda coorte, n = 133). Foram realizadas as genotipagens dos polimorfismos CYP2C9*2, CYP2C9*3 e VKORC1 (c.G1639A). A derivação do algoritmo foi realizada utilizando os dados dos pacientes da primeira coorte com dose estável (n=368) e foi replicado utilizando os dados dos pacientes provenientes da segunda coorte (n=133). Como resultado o algoritmo desenvolvido neste trabalho alcançou um coeficiente de determinação de 40%, incluindo as variáveis: idade, sexo, peso, altura, raça autodeclarada, uso de amiodarona, uso de indutores enzimáticos, os genótipos na VKORC1 (c.G1639A) e os fenótipos de acordo com polimorfismos CYP2C9. Os dados sugerem que o nosso algoritmo desenvolvido é mais acurado do que o algoritmo IWPC (The International Warfarin Pharmacogenetics Consortium) quando a aplicação é focada em pacientes brasileiros. Os algoritmos farmacogenéticos estimadores de dose de varfarina desenvolvidos para uma população específica podem ser mais efetivos para a terapia com varfarina em comparação com o uso de algoritmos estimadores de dose atualmente disponíveis
Warfarin is the most prescribed oral anticoagulant in the world. Pharmacogenetic algorithms have been developed to estimate the dose of warfarin. The main aims of the present study were to develop a pharmacogenetic-based warfarin dosing algorithm and compare algorithm developed in this study with others algorithms available in the literature. We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). Polymorphisms were genotyped in the CYP2C9 * 2, CYP2C9 * 3 and VKORC1 (c.G1639A). The derivation of the algorithm was performed using the data from the patients in the first cohort with a stable dose (n = 368) and was replicated using data from patients from the second cohort (n = 133). Our algorithm achieved a determination of coefficient of 40%, including variables: age, sex, weight, height, self-declared race, use of amiodarone, use of enzymatic inducers, genotypes in VKORC1 (c.G1639A) and phenotypes according to CYP2C9 polymorphisms. Our data suggest that the developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Pharmacogenetics- based warfarin dosing algorithms developed for a specific population may lead to improved performance compared use dosing algorithms currently available

Warfarin is the most widely prescribed oral anticoagulant used for the long-term treatment and prevention of thromboembolic events. Its administration is challenging as it may result in bleeding-related deaths, inadequate anticoagulation and fetal teratogenesis, including fetal warfarin syndrome. A number of environmental and genetic factors contribute to interindividual warfarin dosage variability. The CYP2C9 and VKORC1 genes explain 40- 50% of this variability. The aim of this study was to determine the frequency of known and any new variants in these genes in the SA black population, and correlate these variants and a small subset of environmental factors to dosage variability and pregnancy outcomes. I sequenced the exons and intron/exon boundaries of the CYP2C9 and VKORC1 genes in 100 random black control and 113 patient samples that had at least one pregnancy on warfarin. I observed six previously described CYP2C9 variants, 27 novel CYP2C9 variants, and three previously described VKORC1 variants. 14 of these variants were observed at an allele frequency of 0.02. Of these 14, six appear to decrease (all of which are CYP2C9 variants) and four increase (2 CYP2C9 variants and two VKORC1 variants) warfarin dosage requirement. These 14 CYP2C9 and VKORC1 variants along with a small subset of environmental factors account for 45.3% of warfarin dosage variability in the SA population. I observed an increase in the number of poor pregnancy outcomes in patients on high doses of warfarin. These results allow us to predict the maintenance dose of warfarin in SA black patients better, thereby reducing the risk of adverse effects, and identify those at risk of having a poor pregnancy outcome.

Trabalho final de mestrado em Medicina (Cardiologia), apresentado á Faculdade de Medicina da Universidade de Coimbra
Introdução: Os principais genes implicados na resposta farmacodinâmica e farmacocinética aos dicumarínicos são o gene do citocromo P450 2C9 (CYP2C9) e o da subunidade 1 do complexo da epóxido redutase da vitamina K (VKORC1). Os efeitos dependentes destes polimorfismos na cascata da coagulação podem contribuir para determinar a suscetibilidade individual para as diferentes doenças vasculares. Contudo, existe pouca literatura publicada sobre a eventual associação destes polimorfismos com as patologias vasculares. Objetivos: Avaliar o impacto dos diferentes polimorfismos dos genes CYP2C9 e VKORC1 na ocorrência a médio prazo de hemorragia major e de eventos cardiovasculares e cerebrovasculares. População e Métodos: Análise retrospetiva de uma base de dados unicêntrica constituída por 92 doentes cronicamente anticoagulados com dicumarínicos por patologia cardíaca e, previamente submetidos a um estudo genético para os polimorfismos de suscetibilidade aos dicumarínicos (CYP2C9 e VKORC1). No grupo de doentes anticoagulados por fibrilhação auricular (FA) (n=47), foi realizado um seguimento clínico mediano de 5,8 anos para avaliar a ocorrência de hemorragia major e de eventos cardio e cerebrovasculares. Construiu-se um endpoint composto que incluiu AVC isquémico, SCA e morte e um endpoint AVC isquémico global correspondente à prevalência global de AVC isquémico antes do início da anticoagulação oral e durante o seguimento clínico. Para a análise dos eventos definiram-se, para o gene CYP2C9, 2 sub-grupos: CYP2C9 1/1 e CYP2C9 não 1/1, incluindo este último os doentes heterozigóticos e os homozigóticos para os alelos 2 e 3. Resultados: Dos 92 doentes estudados, 51 (55,4%) eram do sexo masculino, sendo a idade média da população de 66 anos. A maioria dos doentes estava anticoagulada por FA (57,3%). Os genótipos mais frequentes foram o CYP2C9 1/1 e o VKORC1 G/A. Quanto ao gene CYP2C9, a incidência de hemorragia major, de AVC isquémico, do endpoint composto e da morte foi numericamente superior no grupo de doentes com CYP2C9 não 1/1 comparativamente com o grupo de doentes com CYP2C9 1/1, apesar de a diferença não ter atingido significância estatística. A SCA ocorreu com maior frequência no grupo de doentes CYP2C9 1/1 em relação ao grupo de doentes não 1/1, sem diferença estatisticamente significativa. Relativamente aos polimorfismos do gene VKORC1 e à ocorrência de eventos, também não se detetaram diferenças com significado estatístico. Contudo, verificou-se que a hemorragia major e o endpoint composto ocorreram com maior frequência no genótipo GG do que no GA e no AA, enquanto que a morte foi mais frequente nos heterozigóticos para o alelo A. A incidência de SCA foi numericamente superior no genótipo AA do que no GG e GA. A ocorrência de AVC hemorrágico não se verificou em nenhum dos grupos de doentes com FA. Na população total estudada e no sub-grupo de doentes com FA, os genótipos CYP2C9 não homozigóticos para o alelo *1 estiveram associados, respetivamente, a um risco 10 e 6 vezes superior de AVC isquémico, comparativamente ao genótipo homozigótico 1/1. Conclusão: Na população de doentes com FA estudada, não foi observada interação entre o tipo de genótipo CYP2C9 e VKORC1 e a incidência de hemorragia major ou dos eventos cardiovasculares e cerebrovasculares estudados. No entanto, a prevalência global de AVC isquémico foi significativamente superior nos doentes com genótipo CYP2C9 não 1/1
Introduction: The key genes involved in the pharmacokinetics and pharmacodynamics response to dicumarinics are the gene of cytochrome P450 2C9 (CYP2C9) and the subunit 1 of K vitamin’s epoxide reductase complex (VKORC1). The dependent effects of these polymorphisms in the coagulation cascade can help to determine the individual susceptibility to different vascular diseases. However, there is little published literature on the possible association of these polymorphisms with vascular pathologies. Objectives: To evaluate the impact of different polymorphisms of the CYP2C9 and VKORC1 genes in the medium term occurrence of major bleeding, cardiovascular and cerebrovascular events. Methods: Retrospective analysis of a database with 92 patients chronically anticoagulated with dicumarinics for cardiac disease and previously submitted to genetic testing for polymorphisms with susceptibility to dicumarinics (CYP2C9 and VKORC1). In the group of patients anticoagulated for atrial fibrillation (AF) (n = 47), a mean clinical follow-up of 5.8 years was conducted to assess the occurrence of major bleeding and cardiovascular and cerebrovascular events. A composite endpoint that included ischemic stroke, ACS and death and another global ischemic stroke endpoint before oral anticoagulation and during follow-up were constructed. Two sub-groups: CYP2C9 1/1 and CYP2C9 non 1/1 were defined for the CYP2C9 gene allowing the analysis of the events, the latter sub-group included heterozygote and homozygote patients for the alleles 2 and 3. Results: Of the 92 studied patients, 51 (55.4 %) were male, with a mean age of 66 years. Most of the patients were anticoagulated due to AF (57.3%). The most common genotypes were CYP2C9 1/1 and VKORC1 G/A. As for the CYP2C9 gene, the incidence of major bleeding, ischemic stroke, the composite endpoint and death was numerically higher in the group of patients with CYP2C9 non 1/1 when compared with the group of patients with CYP2C9 1/1, but the differences were not statistically significant. ACS was more frequent in the group of patient with CYP2C9 1/1 without statistically significant difference. Regarding the VKORC1 polymorphisms and the occurrence of events, the differences had also no statistical significance. However, major bleeding and the composite endpoint occurred more frequently in the GG genotype than in the GA or AA, whereas death was more frequent in heterozygotes for the allele A. The incidence of ACS was numerically higher in AA genotype than in GG and GA. Among the entire population and in the subgroup of patients with AF, CYP2C9 non homozygous genotypes for the allele * 1 were associated with a 10 and 6 times higher risk of ischemic stroke when compared to homozygous genotype 1/1, respectively. Conclusion: In the studied population of patients with AF, no interaction was observed between the type CYP2C9 and VKORC1 genotypes and the incidence of major bleeding or cardiovascular and cerebrovascular events. However, the overall prevalence of ischemic stroke was significantly higher in patients with CYP2C9 non 1/1 genotype