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Chowdhury, MSI Tipu, Md Fakhrul Islam Khaled, Sadia Sultana, Mohammad Walidur Rahman, MRM Mandal, Khurshed Ahmed, and Harisul Hoque. "Validation of Pharmacogenetic Testing Before Initiation of Warfarin Therapy." University Heart Journal 15, no. 2 (August 19, 2019): 74–78. http://dx.doi.org/10.3329/uhj.v15i2.42665.
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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
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Schaafhausen, Anne, Simone Rost, Johannes Oldenburg, and Clemens Müller. "Identification of VKORC1 interaction partners by split-ubiquitin system and coimmunoprecipitation." Thrombosis and Haemostasis 105, no. 02 (2011): 285–94. http://dx.doi.org/10.1160/th10-07-0483.
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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.
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Sipeky, Csilla, and Béla Melegh. "Haplogroup analysis of vitamin-K epoxide reductase (VKORC1) gene: novel element in the optimization of anticoagulant therapy." Orvosi Hetilap 149, no. 39 (September 1, 2008): 1839–44. http://dx.doi.org/10.1556/oh.2008.28456.
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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.
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Geisen, Christof, Matthias Watzka, Katja Sittinger, Beate Luxembourg, Michael Steffens, Clemens R. Müller, Thomas F. Wienker, Edelgard Lindhoff-Last, Erhard Seifried, and Johannes Oldenburg. "Pharmacogenetics of Oral Anticoagulation - VKORC1-Haplotypes Determine the Inter-Individual and Inter-Ethnical Variability." Blood 108, no. 11 (November 16, 2006): 719. http://dx.doi.org/10.1182/blood.v108.11.719.719.
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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.
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Oldenburg, Johannes, Simone Rost, Andreas Fregin, Christof Geisen, Vytautas Ivaskevicius, Erhard Seifried, Inge Scharrer, et al. "Mutations in the VKORC1 Gene Cause Warfarin Resistance, Warfarin Sensitivity and Combined Deficiency of Vitamin K Dependent Coagulation Factors." Blood 104, no. 11 (November 16, 2004): 277. http://dx.doi.org/10.1182/blood.v104.11.277.277.
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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.
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Jakjovski, Krume, Nikola Labachevski, Aleksandar Petlichkovski, Aleksandar Senev, Jasmina Trojacanec, Emilija Atanasovska, Elena Kostova, and Mirko Spiroski. "Distribution of CYP2C9 and VKORC1 Gene Polymorphisms in Healthy Macedonian Male Population." Open Access Macedonian Journal of Medical Sciences 1, no. 1 (December 15, 2013): 1–5. http://dx.doi.org/10.3889/oamjms.2013.001.
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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.
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Eddine El Mokhtari, Nour, Boris Ivandic, Jens Müller, Stefan Schreiber, Matthias Watzka, Almut Nebel, and Johannes Oldenburg. "Functional promoter polymorphism in the VKORC1 gene is no major genetic determinant for coronary heart disease in Northern Germans." Thrombosis and Haemostasis 97, no. 06 (2007): 998–1002. http://dx.doi.org/10.1160/th06-11-0643.
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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.
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Ferron, Mathieu, Julie Lacombe, Amélie Germain, Franck Oury, and Gérard Karsenty. "GGCX and VKORC1 inhibit osteocalcin endocrine functions." Journal of Cell Biology 208, no. 6 (March 9, 2015): 761–76. http://dx.doi.org/10.1083/jcb.201409111.
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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.
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Harrington, Dominic, Sarah Underwood, Colin Morse, Martin Shearer, Edward Tuddenham, and Andrew Mumford. "Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1." Thrombosis and Haemostasis 93, no. 01 (2005): 23–26. http://dx.doi.org/10.1160/th04-08-0540.
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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.
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Kantemirova, Bela I., Elena N. Chernysheva, Ekaterina A. Orlova, Musalitdin A. Abdullaev, Olga V. Petrova, and Giorgi A. Rostoshvili. "The effect of polymorphic alleles carriage of the VKORC1 gene on clinical and laboratory parameters in patients with acute coronary syndrome." Kazan medical journal 103, no. 5 (October 3, 2022): 737–43. http://dx.doi.org/10.17816/kmj2022-737.
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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.
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AL-Eitan, Laith, Ayah Almasri, and Rame Khasawneh. "Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy." Genes 9, no. 12 (November 27, 2018): 578. http://dx.doi.org/10.3390/genes9120578.
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Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.
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Holail, Jasmine, Reem Mobarak, Bandar Al-Ghamdi, Ahmad Aljada, and Hana Fakhoury. "Association of VKORC1 and CYP2C9 single-nucleotide polymorphisms with warfarin dose adjustment in Saudi patients." Drug Metabolism and Personalized Therapy 37, no. 4 (April 4, 2022): 353–59. http://dx.doi.org/10.1515/dmpt-2022-0108.
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Abstract Objectives Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. Methods This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. Results Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. Conclusions Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.
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Тийс, Р. П., Л. П. Осипова, Е. Н. Воронина, and М. Л. Филипенко. "Population frequencies of vkorc1 c1173t polymorphism, which determining the organism sensitivity to warfarin, in forest nenets and nganasans of northern siberia." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 2() (February 27, 2020): 35–42. http://dx.doi.org/10.25557/2073-7998.2020.02.35-42.
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Полиморфизм C1173T гена VKORC1 является одним из ключевых факторов, определяющих как этнические, так и индивидуальные различия в чувствительности к антикоагулянту варфарину и его поддерживающей дозе у пациентов при лечении тромбозозависимых заболеваний. В связи с этим, на популяционном уровне проведено исследование полиморфизма VKORC1 C1173T среди коренных представителей лесных ненцев Ямало-Ненецкого автономного округа и нганасан полуострова Таймыр Красноярского края. Генотипирование однонуклеотидных замен в гене VKORC1 проводилось в режиме реального времени с использованием конкурирующих TaqMan-зондов. Выявлено, что вариант VKORC1 1173T встречается с высокой частотой в изученных популяциях: 67% у лесных ненцев и 94% у нганасан. Этот показатель существенно и статистически значимо выше, чем у европейцев, и имеет схожий характер распространения с таковым у азиатов Китая и Японии. Результаты нашего исследования расширяют знания о полиморфизме гена VKORC1 в человеческих популяциях, а также способствуют развитию персонализированной медицины по отношению к коренным жителям Сибири, так как генетический статус человека, имеющего вариант 1173T, может учитываться в целях достижения максимально безопасной и эффективной терапии варфарином при тромбозозависимых заболеваниях. Polymorphism C1173T of the VKORC1 gene is one of the key factors determining both ethnic and individual differences in the sensitivity to the anticoagulant warfarin and its maintenance dose in patients in the treatment of thrombosis-dependent diseases. In this regard, at the population level the VKORC1 C1173T polymorphism was studied in indigenous populations of the Forest Nenets (the Yamal-Nenets Autonomous Okrug) and Nganasans (the Taimyr Peninsula of the Krasnoyarsk region). Genotyping of C1173T single nucleotide substitution in the VKORC1 gene was carried out in real time using competing TaqMan probes. It was revealed that the variant VKORC1 1173T occurs with a high frequency in the studied populations: 67% in Forest Nenets and 94% in Nganasans. This indicator is significantly higher than that of Europeans, and has a similar distribution pattern with that of Asians. The results of our study expand knowledge about VKORC1 gene polymorphism in human populations, and also promote the development of personalized medicine in relation to indigenous people of Siberia, since the genetic status of a person with variant 1173T can be taken into account at an individual level in order to achieve the most safe and effective warfarin therapy of thrombosis-dependent diseases.
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Zohir, Naguib, Reham Afifi, Asmaa Ahmed, Zinab Aly, Mehry Elsobekey, Heba Kareem, and Rehab Helmy. "Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study." Open Access Macedonian Journal of Medical Sciences 1, no. 1 (December 15, 2013): 76–82. http://dx.doi.org/10.3889/oamjms.2013.015.
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Background: Oral anticoagulant therapy is conditioned by environmental and genetic factors.Objectives: To verify the effect of the calumenin, cytochrome P-450 variants and VKORC1 genetic polymorphisms on the response to warfarin therapy and warfarin dose adjustment.Patients and Methods: We selected fifty warfarin treated patients with dose adjusted at INR value between 2 and 3. PCR-RFLP is used for of calumenin gene polymorphism. Insitu Hybridization was used for identification of VKORC1 promoter and CYP2C9 variants polymorphisms.Results: The warfarin dose in the patients with Calumenin and CYP2C9 genetic polymorphism was lower than the wild type gene. The warfarin dose in the patients with VKORC1 variants was statistically lower compared to that of the wild-type. The presence of combined CYP2C9 genetic variants and VKORC1 polymorphism was associated with lower warfarin dose than that the wild types.Conclusion: Calumenin (CALU) might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy.
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Lichy, Christoph, Inge Werner, Alexander Radbruch, Simone Wagner, Caspar Grond-Ginsbach, and Marie-Luise Arnold. "Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population." Thrombosis and Haemostasis 100, no. 10 (2008): 614–17. http://dx.doi.org/10.1160/th07-10-0617.
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SummaryVariation in the gene that encodes the vitamin K epoxide reductase subunit 1 (VKORC1) was recently proposed as a genetic risk factor for stroke in a Chinese population. In this ethnic group, only two common haplotypes were observed, with the C-allele of the polymorphism rs2359612 (VKORC1: c.283+837C>T) associated with stroke and other cardiovascular diseases. Recently, the influence of VKORC1 haplotypes on venous thrombosis and coronary heart disease was analyzed in study populations from France and Northern Germany. We studied the frequencies of theVKORC1 haplotypes in a series of young (<50 years, n = 158) patients with ischemic stroke from Southern Germany. The data were compared with findings from age-matched healthy control subjects from the same population (n = 213). In a replica study we also analysed older stroke patients (>50 years, n = 135) and matched control subjects (n = 113). Neither in the young population, nor in the replica study, we observed significant differences in VKORC1 haplotype distributions between healthy control subjects and patients with ischemic stroke. Our data do not confirm the association between polymorphism in the VKORC1 gene and stroke in the German population.
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Palacio, Lina, Diana Falla, Ignacio Tobon, Fernando Mejia, John E. Lewis, Ariel F. Martinez, Mauricio Arcos-Burgos, and Mauricio Camargo. "Pharmacogenetic Impact of VKORC1 and CYP2C9 Allelic Variants on Warfarin Dose Requirements in a Hispanic Population Isolate." Clinical and Applied Thrombosis/Hemostasis 16, no. 1 (June 29, 2009): 83–90. http://dx.doi.org/10.1177/1076029608330472.
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Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 ± 0.50 mg/d), intermediate (4.2 ± 0.76 mg/d), and resistant (7.40 ± 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele *1 compared to those individuals with variants composed of other alleles (P = .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P = .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C9*1, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.
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Giraldo-Ocampo, Sebastian, Lorena Diaz-Ordoñez, Yisther Katherine Silva-Cuero, Juan David Gutierrez-Medina, Estephania Candelo, Javier A. Diaz, and Harry Pachajoa. "Frequency of polymorphisms in the CYP2C9, VKORC1, and CYP4F2 genes related to the metabolism of Warfarin in healthy donors from Cali, Colombia." Medicine 102, no. 30 (July 28, 2023): e34204. http://dx.doi.org/10.1097/md.0000000000034204.
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Alleles in the VKORC1, CYP2C9, and CYP4F2 genes can influence Warfarin dose requirement. We aimed to determine the frequency of the polymorphisms in these genes in healthy individuals from Cali, Colombia. Observational study where total blood was collected from 107 healthy donors who attended a higher educational institution in Cali, Colombia. Sanger sequencing of exons 2, 3, 5, and 7 of the CYP2C9 gene; the common promoter region of CYP (rs12777823); exon 11 of CPY4F2 and the polymorphism c.-1639G > A in the VKORC1 gene promoter was performed. CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*9, CYP2C9*11, CYP4F2*3, rs12777823, and VKORC1*2 were detected. The latter had the highest frequency with 80 (74.8%) participants in a heterozygous or homozygous state. The least frequent allele was CYP2C9*11 with only 1 carrier. Combined haplotypes (VKORC1 *1/*2 or *2/*2 and CYP2C9 *1/*2 or *2/*2) were identified in 14 (13.7%) subjects. Both frequencies found in the VKORC1 and CYP2C9 alleles were similar to the ones reported for Latin Americans of European and Native American Ancestry. VKORC1*2 allele, the main genetic contributor to Warfarin dosing requirement, was the variant with the highest frequency (74.8% subjects, with a frequency of the alternative allele (A) of 50%). Our findings provide researchers with a greater insight regarding the frequency of common polymorphisms that affect anticoagulation treatment in the Cali (Colombia) population.
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YAY, Kerem, Alper İbrahim TOSYA, and Zafer Cengiz ER. "DO VKORC1 AND CYP2C9 MUTATIONS LEAD TO WARFARIN RESISTANCE?" Euroasia Journal of Mathematics, Engineering, Natural & Medical Sciences 8, no. 18 (November 25, 2021): 100–104. http://dx.doi.org/10.38065/euroasiaorg.768.
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The objective of this study was to determine the influence of VKORC1 and CYP2C9 polymorphisms on warfarin resistant patients. Warfarin resistance is described as the inability to prolong the prothrombin time or raise the INR up to the 2 therapeutic range when the drug is given at typically doses. Polymorphisms may play a role as some VKORC1 and CYP2C9 variant alleles are known to be associated with these circumstances. 28 patients who were taking warfarin more than 15 mg/day and had INR values below 2.1 and had thromboembolic events while using warfarin were enrolled in this study. Heterozygote mutation in the VKORC1 gene was identified in 15 of 28 patients. Seven patients had heterozygote mutation of the CYP2C9 gene, and that may correspond to the ultrarapid metabolism of warfarin. VKORC1 and CYP2C9 polymorphism contribute to the difference in dose requirement amongst the patients, but other additional possible factors may play a role in different races. We suggest that medicians may use this tests before starting warfarin therapy and shape the treatment course according to this results.
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Herman, Darja, Polona Peternel, Mojca Stegnar, Katja Breskvar, and Vita Dolzan. "The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement." Thrombosis and Haemostasis 95, no. 05 (2006): 782–87. http://dx.doi.org/10.1160/th05-10-0678.
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SummaryThe degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G>A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose.The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p=0.032). Common polymorphism (6484C>T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95 - 6.45), 3.49 (3.07 - 3.90) and 2.11 (1.80 - 2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p<0.001). In contrast, 9041G>A polymorphism in 3’UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58 - 3.60), 4.26 (3.69 - 4.82) and 5.86 (4.53 - 7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p<0.001).With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9,VKORC1), age and body-surfacearea. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.
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Samama, Michel-Meyer M. M., Laurent L. Bodin, Marie Helene M. H. Horellou, Florence F. Parent, Anne A. Kereveur, Philippe P. Beaune, Marie Anne M. A. Loriot, and Jacqueline J. Conard. "Presence of a T383G Mutation in the Vitamin K Epoxide Reductase Gene (VKORC1) in a Patient Resistant to Four Different Vitamin K Antagonists." Blood 104, no. 11 (November 16, 2004): 4068. http://dx.doi.org/10.1182/blood.v104.11.4068.4068.
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Abstract Resistance to vitamin K antagonists is a rare disorder which until recently has not been associated to a genetic factor. The existence of inherited warfarin resistant rat strains has been related to mutations of the genes involved in the vitamin K cycle. Vitamin K dependent carboxylase was cloned in 19911, while human vitamin K epoxide reductase complex 1 (VKORC1), another enzyme implicated in vitamin K cycle, has been cloned more recently2,3. Mutations in this gene are responsible for both human and rat warfarin resistance 3. In 1997, we reported 4 a 63-year old patient with recurrent pulmonary embolism and deep vein thrombosis without known hereditary or acquired thrombophilia who was found resistant to warfarin (up to 45mg/day), fluindione (up to 80mg/day), acenocoumarol (up to 12 mg/day) and phenprocoumon (up to 30 mg/day). With phenprocoumon, long-acting vitamin K antagonist, drug concentration reached 85 mg/L (usual range 1–5 mg/L) but the INR remained around 1. Daily low molecular weight heparin (LMWH) was continued 3 months. Treatment was discontinued on 2 occasions and a recurrent thrombotic episode was observed. The patient is now receiving a single daily dose of low molecular weight heparin (80 mg Enoxaparin, body weight 120 kg, 67 IU/kg once a day) for the past 10 years without thrombotic or bleeding episodes. Osteodensitometry remains normal after 9 years of treatment. Careful biochemichal investigation had demonstrated a deficiency in vitamin K dependent carboxylation and absence of blockade of vitamin K epoxide reductase by phenprocoumon. This year, we sequenced the three exons of VKORC1 in this patient and detected a heterozygous T383G transversion resulting in a leucine to arginine substitution (L128R). This mutation has been recently identified by Rost3 et al. in an individual with warfarin resistance. It was not found in 259 control subjects that we had tested. Interestingly, another gene mutation of the VKORC1 can be responsible for a combined deficiency of vitamin K dependent clotting factors 3. In conclusion, a resistance to all vitamin K antagonists, including warfarin up to 45 mg/day is extremely rare and the mutation T383G of the VKORC gene has been reported in only one patient before the case reported here. Testing for mutation in VKORC1 will help in explaining some cases of anti vitamin K resistance.
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Ozbayer, Cansu, Hulyam Kurt, Medine Nur Kebapci, Didem Turgut Cosan, Ertugrul Colak, Hasan Veysi Gunes, and Irfan Degirmenci. "Lack of Association Between Type 2 Diabetes and the 3673G / A and 9041G / A Gene Variants of Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1)." International Journal for Vitamin and Nutrition Research 86, no. 3-4 (June 2016): 133–39. http://dx.doi.org/10.1024/0300-9831/a000302.
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The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene is expressed in many tissue types, and encodes the VKORC1 protein, which is a key enzyme in the vitamin K cycle. Although researchers have focused on the effects of vitamin K on glucose metabolism, and on its role in the development of type 2 diabetes (T2DM), no consensus has yet been reached. Therefore, here we aimed to investigate the association between VKORC1 variants and the risk of T2DM. The 3673G / A (rs9923231) and 9041G / A (rs7294) VKORC1 variants were investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 100 control individuals and 100 patients with T2DM. The genomic regions were amplified by PCR; amplicons were digested using the AciI and NciI enzymes and visualized by agarose gel electrophoresis. The genotype frequencies of the 3673G / A variants were GG (22%), GA (56%), and AA (22%) in the control group and GG (19%), GA (52%), and AA (29%) in patients with T2DM (p > 0.05). The genotype frequencies of the 9041G / A variants were GG (37%), GA (53%), and AA (10%) in the control group and GG (46%), GA (45%), and AA (9%) in patients with T2DM (p > 0.05). In conclusion, we found no significant correlation between the control group and patients with T2DM, with regard to the different genetic models of the 3673G / A and 9041G / A variants. These data suggest that these VKORC1 gene variants may not be linked to T2DM.
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Czogalla, K. J., M. Watzka, and J. Oldenburg. "VKCFD2 – from clinical phenotype to molecular mechanism." Hämostaseologie 36, S 02 (2016): S13—S20. http://dx.doi.org/10.1055/s-0037-1617062.
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SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.
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Wu, Weidong, Job Harenberg, Christel Weiss, Julia Kirchheiner, Simone Stehle, Uwe Fuhr, and Christoph Gleiter. "Influence of Genetic Polymorphisms of VKORC1 and CYP2C9 in Patients on Phenprocoumon Steady-State Dose Requirements." Blood 112, no. 11 (November 16, 2008): 4051. http://dx.doi.org/10.1182/blood.v112.11.4051.4051.
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Abstract The variants of the (Vitamin-K epoxid reductase subcomplex 1) VKORC1 and of cytochrome P450 2C9 (CYP2C9) genes are know to influence the steady state dose of the vitamin-K antagonist (VKA) phenprocoumon during oral anticoagulant therapy. We have analysed in detail the influence of the VCORC1 1173CC and 1173CT variants in combination with the CYP2C9 variants on the steady state dose of phenprocoumon. The weekly phenprocoumon dosage was calculated after a 3 to 6 months of stable anticoagulation by the international normalized ratio (INR) which had to be in a range from 2 to 3 in 114 patients. VKORC1 1173CC, CT, TT and CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 genotypes were determined using direct DNA sequencing and realtime PCR. Patients carrying VKORC1 1173CT and CYP2C9*1/*1 genotypes required a 33% lower steady state dose of phenprocoumon compared to VKORC1 1173CC and CYP2C9*1/*1 genotypes (p=0.0001). Patients with VKORC1 1173CC in combination with CYP2C9*1/*2, *1/*3 needed 10% and 34% lower steady state dose of phenprocoumon compared to the combination with CYP2C9*1/*1, respectively (p=0.0001). Patients carrying VKORC1 1173CT needed lower doses of phenprocoumon in combination with CYP2C9*1/*1 (−32%), *1/*2 (−29%), or *1/*3 (−33%), and VKORC1 1173TT in combination with CYP2C9*1/*3 (−44%) compared to VKORC1 1173CC combined with CYP2C9*1/*1 (all p<0.001). CYP2C9 variants did not influence the dose of carriers of VKORC1 1173CT gene. Both genotypes together influenced the phenprocoumon maintenance dosage in this naturalistic study design. Genotyping for CYP2C9 and VCORC1 therefore might be a suitable tool for dose individualization in patients at oral anticoagulant drug therapy.
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D'Andrea, Giovanna, Rosa Lucia D'Ambrosio, Pasquale Di Perna, Massimiliano Chetta, Rosa Santacroce, Vincenzo Brancaccio, Elvira Grandone, and Maurizio Margaglione. "A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin." Blood 105, no. 2 (January 15, 2005): 645–49. http://dx.doi.org/10.1182/blood-2004-06-2111.
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AbstractPatients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln, were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3′ untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P = .002) or the TT genotype (3.5 mg; P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r2, 0.353) of the interindividual variability. Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity.
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Rakicevic, Ljiljana, Mirjana Kovac, Dragica Radojkovic, and Milica Radojkovic. "The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance." Srpski arhiv za celokupno lekarstvo, no. 00 (2022): 13. http://dx.doi.org/10.2298/sarh211118013r.
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Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.
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Lin, Xianliang, Hao Chen, Le Ni, Yunqiang Yu, Zhurong Luo, and Lihong Liao. "Effects of EPHX1 rs2260863 polymorphisms on warfarin maintenance dose in very elderly, frail Han-Chinese population." Pharmacogenomics 21, no. 12 (August 2020): 863–70. http://dx.doi.org/10.2217/pgs-2020-0054.
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Aim: This study was conducted to investigate the effects of VKORC1, CYP2C9, CYP4F2 and EPHX1 and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population. Materials & methods: 16 variants of VKORC1, CYP2C9, CYP4F2 and EPHX1 were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Results & conclusion: EPHX1 rs2260863 nonvariant CC homozygotes required significantly lower daily warfarin dose than GC heterozygotes. In the multivariable model, VKORC1 rs9923231, CYP2C9 rs1057910, EPHX1 rs2260863, CYP4F2 rs2189784 and body surface area altogether explained 26.9% of dosing variability. This study revealed the main impact of genetic factors on warfarin response in this special population.
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Wadelius, Mia, Leslie Y. Chen, Jonatan D. Lindh, Niclas Eriksson, Mohammed J. R. Ghori, Suzannah Bumpstead, Lennart Holm, Ralph McGinnis, Anders Rane, and Panos Deloukas. "The largest prospective warfarin-treated cohort supports genetic forecasting." Blood 113, no. 4 (January 22, 2009): 784–92. http://dx.doi.org/10.1182/blood-2008-04-149070.
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Abstract Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 × 10−34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 × 10−100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.
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Gong, Inna Y., Rommel G. Tirona, Ute I. Schwarz, Natalie Crown, George K. Dresser, Samantha LaRue, Nicole Langlois, et al. "Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy." Blood 118, no. 11 (September 15, 2011): 3163–71. http://dx.doi.org/10.1182/blood-2011-03-345173.
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Abstract Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P = .52, P = .28) and risk of overanticoagulation (P = .64, P = .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.
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Drent, Marjolein, Petal Wijnen, Otto Bekers, and Aalt Bast. "Is a Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism a Risk Factor for Nephrolithiasis in Sarcoidosis?" International Journal of Molecular Sciences 25, no. 8 (April 18, 2024): 4448. http://dx.doi.org/10.3390/ijms25084448.
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Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79–33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.
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Sambyalova, A. Yu, T. A. Bairova, E. V. Belyaeva, O. A. Ershova, D. S. Sargaeva, and S. I. Kolesnikov. "CYP2C9, CYP4F2, VKORC1 Gene Polymorphism in Buryat Population." Russian Journal of Genetics 56, no. 12 (December 2020): 1496–503. http://dx.doi.org/10.1134/s1022795420120121.
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Soltani Banavandi, Mohammad Javad, and Naghmeh Satarzadeh. "Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province." Pharmacogenomics Journal 20, no. 4 (January 6, 2020): 574–78. http://dx.doi.org/10.1038/s41397-019-0146-5.
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Wang, Danxin, Huizi Chen, Kathryn M. Momary, Larisa H. Cavallari, Julie A. Johnson, and Wolfgang Sadée. "Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement." Blood 112, no. 4 (August 15, 2008): 1013–21. http://dx.doi.org/10.1182/blood-2008-03-144899.
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Abstract Warfarin dose requirements have been associated with 2 main haplotypes in VKORC1, but the responsible polymorphisms remain unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B lymphocytes. The observed 2-fold allelic mRNA expression imbalance narrowed possible candidate SNPs to −1639G>A and 1173C<T. This genotype effect was observed selectively in the liver but not in heart or lymphocytes. In vitro expression of VKORC1 gene constructs, including coding and promoter regions, failed to reveal any genotype effect on transcription and mRNA processing. Chromatin immunoprecipitation with antibodies against acetyl-histone3 and K4-trimethyl-histone3 revealed preferential association of the promoter −1639 G allele with active chromatin, consistent with enhanced mRNA expression. The minor −1639 A allele generates a suppressor E-box binding site, apparently regulating gene expression by a mechanism undetectable with reporter gene assays. A clinical association study demonstrated that promoter SNP −1639G>A, and the tightly linked intron1 SNP 1173C>T, predict warfarin dose more accurately than intron 2 SNP 1542G>C in blacks. Increased warfarin dose requirement in blacks was accounted for by lower frequency of the −1639 A allele. Therefore, −1639G>A is a suitable biomarker for warfarin dosing across ethnic populations.
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Babiker, Rowida, Salah Eldin Gumaa Elzaki, Amanda G. Elgoraish, and Hussam Ali Osman. "Association of Cytochrome P4502C9, Vitamin K Epoxide Reductase and Gamma-Glutamyl Carboxylase Gene Polymorphisms with Warfarin Dose Requirement Among Sudanese Patients." International Journal of Innovative Research in Medical Science 8, no. 04 (April 7, 2023): 140–46. http://dx.doi.org/10.23958/ijirms/vol08-i04/1642.
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Background: Warfarin is a common anticoagulant drug that has a narrow therapeutic index; a higher dose causes excessive bleeding and a lower dose leads to cerebrovascular clotting and stroke in patients. The management of warfarin therapy is challenging because there is variability in patient response due to many factors. Genetic factors that are most relevant, such as CYP2C9, and andVKOR, are the target site for warfarin. The study aimed to investigate the association between CYP2C9*2, VKORC1 (-1639 G>A), and GGCX T>G polymorphisms with warfarin daily dose in Sudanese patients on warfarin treatment referred to anti-coagulation clinics in Khartoum State, Sudan. Method: A cross-sectional descriptive study was conducted on randomly selected 107 patients on warfarin with different clinical indications. Their genotype was analyzed by Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) to determine the polymorphisms. Result: The study revealed that CYP2C9 genotype wild type was more frequent than heterozygote. For VKORC1 the frequency of the A allele was 61.8% and for the G allele was 38.2%, the GGCX genotype was observed only in wild-type and homozygous genotypes (89.7%& 10.3%, respectively). The t allele of GGCX was higher than the G alleles. Conclusion: The most common polymorphisms that revealed high significance on warfarin dose determination were VKORC1A/giving evidence to new guidelines dose requirements according to the patient genotype. These new dose requirement recommendations may lead to a significant improvement in the management of anticoagulant therapy in Sudan.
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Groza, Ioana, Dana Matei, Marcel Tanţău, Adrian P. Trifa, Sorin Crişan, Ştefan C. Vesa, Corina Bocşan, Anca D. Buzoianu, and Monica Acalovschi. "VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding." Journal of Gastrointestinal and Liver Diseases 26, no. 1 (March 1, 2017): 13–18. http://dx.doi.org/10.15403/jgld.2014.1121.261.vko.
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Background & Aims: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists.Methods: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism.Results: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001).Conclusion: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB.
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Groza, Ioana, Dana Matei, Marcel Tanţău, Adrian P. Trifa, Sorin Crişan, Ştefan C. Vesa, Corina Bocşan, Anca D. Buzoianu, and Monica Acalovschi. "VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding." Journal of Gastrointestinal and Liver Diseases 26, no. 1 (March 1, 2017): 13–18. http://dx.doi.org/10.15403/jgld-882.
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Background & Aims: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists.Methods: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism.Results: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001).Conclusion: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB.
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Li, Wenyan, Ping Zhao, Liwen Chen, Xiaoyin Lai, Guohua Shi, Longxuan Li, and Jing Dong. "Impact of CYP2C9, VKORC1, ApoE and ABCB1 polymorphisms on stable warfarin dose requirements in elderly Chinese patients." Pharmacogenomics 21, no. 2 (January 2020): 101–10. http://dx.doi.org/10.2217/pgs-2019-0139.
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Aim: To analyze the impact of nongenetic factors and gene polymorphisms on warfarin dose requirements in elderly Shanghai Han Chinese patients. Materials & methods: Genotypes of CYP2C9 (rs1799853 and rs1057910), FPGS (rs7856096), ApoE (rs7412 and rs429358), GGCX (rs699664 and rs12714145), EPHX1 (rs4653436, rs1877724, rs1051740 and rs1131873), NQO1 (rs1800566 and rs10517), ABCB1 (rs1045642), VKORC1 (rs9923231) and CYP4F2 (rs2108622) in 214 patients with stable warfarin dose were determined and their demographic characteristics were recorded. Results: Multiple linear regression analysis revealed that VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone could explain 37.0% of the individual variations of daily stable warfarin dose. Conclusion: VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone play an important role in stable dose variation of warfarin in elderly Shanghai Han Chinese patients, whereas ABCB1 rs1045642 is not a significant genetic factor.
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Vesa, Stefan Cristian, Sonia Irina Vlaicu, Vitalie Vacaras, Sorin Crisan, Octavia Sabin, Sergiu Pasca, Adrian Pavel Trifa, Tamas Rusz-Fogarasi, Madalina Sava, and Anca Dana Buzoianu. "CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation." Genes 11, no. 7 (July 20, 2020): 822. http://dx.doi.org/10.3390/genes11070822.
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Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.
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Anekella, Bharathi, Jainlei Wu, Catherine Huang, Sergy Dryga, Tamara Smith, Renee Howell, and Mark Manak. "Characterization and Development of Genomic DNA Quality Controls for Thrombophilia and Warfarin Sensitivity Testing." Blood 112, no. 11 (November 16, 2008): 4679. http://dx.doi.org/10.1182/blood.v112.11.4679.4679.
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Abstract Background: Genetic tests for diagnosis of clotting disorders and monitoring their treatment are based on identification of single nucleotide polymorphisms (SNPs) that are related respectively to clotting and to drug metabolism crucial to the effectiveness of therapy. Thrombophilia, an inherited condition which predisposes to thromboembolism, is due in part to genetic factors, such as the presence of SNPs in the genes encoding clotting factors. Hyperhomocysteinemia, which poses an extremely elevated risk of thromboembolism to the patient, can be caused by certain mutations to the MTHFR (677CT, 1298AC) gene; genotyping all genes involved in thrombophilia concurrently can offer a more complete picture of the genetic component of thrombophilic risk. Warfarin is the most frequently used oral anticoagulant for treatment and prevention of thromboembolism and requires careful adjustment of therapeutic dose and close monitoring because of its narrow therapeutic index and wide individual variability in response and therapeutic dose. Genetic variations in two genes, CYP2C9 and vitamin K epoxide reductase (VKORC1), have been shown to have a profound effect on warfarin sensitivity. Using genetic tests for identification of these variants clinicians to better estimate the appropriate starting dose for therapy, which may improve drug safety. Currently a number of test systems detect these SNPs. Use of a well-characterized independent quality control sample is important to monitor the accuracy and reproducibility of these tests. We have developed multi-analyte quality controls that contain major SNP variants for both thrombophilia MTHFR and warfarin sensitivity. Methods: PBMCs from multiple donors were screened for mutations for MTHFR for Thrombophilia and for CYP2C9 and VKORC1 for warfarin sensitivity. Mutations were identified using the Third Wave Technologies INVADER® and Autogenomics INFINITI™ platforms; and ABI TaqMan® SNP assay. All mutations were confirmed by sequencing on an ABI 3130 instrument. Results: PBMC samples were screened for CYP2C9, VKORC1, and MTHFR mutations. The mutation frequency for CYP2C9*2, CYP2C9*3 and VKORC1 1639GA variants was 28%, 7% and 63% respectively. 100% genotyping concordance was observed in all testing. In addition, heterozygotes for additional VKORC1 SNPs 5808TG, 6484CT, 6853GC, 7566CT, and 9041GA were present in one sample bearing VKORC -1639GA. The mutation frequency for MTHFR 677CT and 1298AC was 17% wt and 29% het for both SNPs. The identification of heterozygotes in several SNPs allowed development of multi-analyte controls for both genes. Data showing reproducibility and accuracy in SNP call rate on various test platforms will be presented. Conclusion: We have developed multi-analyte controls for thrombophilia and warfarin sensitivity that can monitor extraction, amplification and detection, and evaluated their performance with several test methods.
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Bevans, Carville, Andreas Fregin, Christof Geisen, Clemens Müller-Reible, Matthias Watzka, and Johannes Oldenburg. "Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORC1 and CYP2C9 alleles." Thrombosis and Haemostasis 98, no. 09 (2007): 570–78. http://dx.doi.org/10.1160/th07-07-0454.
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SummaryFor decades coumarins have been the most commonly prescribed drugs for therapy and prophylaxis of thromboembolic conditions. Despite the limitation of their narrow therapeutic dosage window, the broad variation of intra- and inter-individual drug requirement, and the relatively high incidence of bleeding complications,prescriptions for coumarins are increasing due to the aging populations in industrialised countries.The identification of the molecular target of coumarins,VKORC1, has greatly improved the understanding of coumarin treatment and illuminated new perspectives for a safer and more individualized oral anticoagulation therapy. Mutations and SNPs within the translated and non-translated regions of the VKORC1 gene have been shown to cause coumarin resistance and sensitivity,respectively. Besides the known CYP2C9 variants that affect coumarin metabolism, the haplotype VKORC1*2 representing a frequent SNP within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity,reducingVKORC1 enzyme activity to 50% of wild type. Homozygous carriers of the VKORC1*2 allele are strongly predisposed to coumarin sensitivity. Using individualized dose adaptation, a significant reduction of bleeding complications can be expected, especially in the initial drug saturation phase. Furthermore, concomitant application of low dose vitamin K may significantly reduce intra-individual coumarin dose variation and, thus, may stabilize oral anticoagulation therapy. The use of new pharmacogenetics-based dosing schemes and the concomitant application of low-dose vitamin K with coumarins will decidedly influence the current practice of oral anticoagulation and greatly improve coumarin drug safety.
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Koshy, Linda, S. Harikrishnan, and PR Sudhakaran. "Prioritizing rs7294 as a mirSNP contributing to warfarin dosing variability." Pharmacogenomics 21, no. 4 (March 2020): 257–67. http://dx.doi.org/10.2217/pgs-2019-0137.
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Aim: The role of mirSNPs in the 3′UTR of VKORC1, CYP2C9 and CYP4F2 genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Methods: Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. Results: MirSNP rs7294 in the 3′UTR of VKORC1 gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. In silico analysis predicted altered hybrid stability for the hsa-miR-133a-3p conserved binding site, providing evidence for miRNA-mediated gene regulation. Conclusion: The results support the inclusion of rs7294 as a functional variable for population-specific dosing algorithms to improve dosing accuracy.
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Rumyantsev, N. A., D. A. Sychev, V. G. Kukes, R. E. Kazakov, A. A. Rumyantsev, and T. V. Taratuta. "Experience of individualization of oral anticoagulants use and dosage in personalized medicine centre conditions." Kazan medical journal 96, no. 6 (December 15, 2015): 1065–68. http://dx.doi.org/10.17750/kmj2015-1065.
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The application of pharmacogenetic testing was analyzed in patients treated at the center of personalized medicine, in order to analyze gene polymorphism frequency - response predictors to indirect anticoagulants therapy, estimation of the warfarin dose selection time, the hospitalization duration. The presence of VKORC1 and CYP2C9 polymorphisms or homozygous polymorphisms combinations is quite common in the Russian population: CYP2C9*2 polymorphism (15.3%) was observed in 8 patients, CYP2C9*3 (9.6%) in 5 patients. VKORC1 gene A allele was detected in 18 patients, accounting for 34.6% of the whole group. In patients with this polymorphism warfarin administration according to the traditional algorithm often leads to excessive anticoagulation and bleeding. Initiation of warfarin therapy according to the scheme taking into account genotyping significantly increases the treatment safety and reduces the adverse events incidence in this group of patients.
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Jiménez-Varo, Enrique, Marisa Cañadas-Garre, María José Gutiérrez-Pimentel, Cristina Isabel Henriques, Ana Margarida Pinheiro, and Miguel Ángel Calleja-Hernández. "Pharmacogenetics role in the safety of acenocoumarol therapy." Thrombosis and Haemostasis 112, no. 09 (2014): 522–36. http://dx.doi.org/10.1160/th13-11-0941.
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SummaryVitamin K antagonists (VKAs) remain as the most prescribed drug for treatment and prevention of thrombotic disorders in many countries, despite the recent approval of the new oral anticoagulants (NOACs). Although effectiveness and safety of VKAs are tightly associated to maintaining the patient within the international normalised ratio (INR) therapeutic range (TWR), they have been likened to NOACs when patients are in good INR control (≥66% of TWR). Therefore, assessing the safety of patients should be a priority in the selection of the anticoagulation therapy. The aim of this study was to evaluate the association between CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2*3, ABCB1 C3435T, APOE, CYP2C19*2 and CYP2C19*17 gene polymorphisms and treatment safety in 128 patients diagnosed with atrial fibrillation or venous thromboembolism during the initial first seven months of acenocoumarol therapy. After the first month, VKORC1-Tallele and APOE-E3/E3 genotype were independently associated to higher time above therapeutic range (TAR) and lower time below the therapeutic range (TBR). After seven months, VKORC1 T-allele predicted higher TAR, and was also associated to increased INR>4, particularly the TT-genotype (odds ratio [OR]: 32; 95% confidence interval [CI95%]: 6–175; p=810–5). C-alleles for CYP2C9*3 (OR: 5.5; CI95%: 1.8–17; p=0.003) and ABCB1 (OR: 8.9;CI95%: 1.1–70; p=0.039) independently influenced on INR>6 . Patients VKORC1-TT/ABCB1-C remained 26.8% [19.7–38.9] TAR, with associated relative risk (RR) for INR>4 1.8 higher (CI95%: 1.2–2.5; p=0.015). Patients VKORC1-TT also presented the highest risk of bleeding events (RR: 3.5;CI95%: 1.4–8.4; p=0,010). In conclusion, VKORC1, CYP2C9*3, APOE and ABCB1 genotypes should be considered in prevention of overanticoagulation and bleeding events in the initiation of acenocoumarol therapy.
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Ghadam, P., F. Sadeghian, R. Sharifian, S. Sadrai, B. Kazemi, and E. Nematipour. "VKORC1 Gene Analysis in an Iranian Warfarin Resistant Patient." Journal of Biological Sciences 8, no. 3 (March 15, 2008): 691–92. http://dx.doi.org/10.3923/jbs.2008.691.692.
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Andriyashkina, D. Yu, A. A. Kondrashov, N. А. Shostak, N. A. Demidova, D. V. Yudin, D. Yu Kulakov, and G. R. Avetisian. "Sneddon syndrome: A rare diagnosis." Rheumatology Science and Practice 60, no. 6 (December 26, 2022): 630–37. http://dx.doi.org/10.47360/1995-4484-2022-630-637.
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The study objective is to demonstrate a rare cause of recurrent acute cerebrovascular diseases in a young patient – Sneddon syndrome. The patient revealed gene polymorphism: homozygous 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene, C807T in the glycoprotein I gene (GPIa), T1565C in the glycoprotein III gene (GPIIIa), G1639A in the vitamin K epoxide reductase gene (VKORC1), increased homocysteine, which were risk factors for thrombosis.
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Connolly, Courtney T., Armida Faella, Timothy C. Nichols, Katherine A. High, Valder R. Arruda, and Paris Margaritis. "VKORc1 Is Under-Expressed in Skeletal Muscle of Humans, Dogs and Mice: Potential Implications for Ectopic Coagulation Factor Expression in Pre-Clinical and Therapeutic Applications." Blood 124, no. 21 (December 6, 2014): 1477. http://dx.doi.org/10.1182/blood.v124.21.1477.1477.
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Abstract Post-translational modifications of coagulation factors in the liver are essential for function. The vitamin K dependent coagulation proteins (VKCPs) require vitamin K to undergo gamma carboxylation of the glutamic residues in their Gla domain by gamma-glutamyl carboxylase [GGCX]. The vitamin K is then recycled by the action of epoxide reductase [VKORc1] and/or quinone reductase [NQO1]. The hemostatic importance of the vitamin K “cycle” is evidenced by patients who may suffer bleeding complications when anticoagulated with warfarin, which targets the vitamin K cycle. Moreover, the ability of a variety of VKCPs to secrete a biologically active product depends on the removal of their propeptide by the action of the intracellular endoprotease furin [FURIN gene]. Previous in vitro work on recombinant coagulation Factor IX, which is used for hemophilia B treatment, has connected these two processing steps by showing that endogenous VKORc1 as well as FURIN can be limiting factors in high-yield expression systems. In vivo, skeletal muscle (in contrast to liver) has been utilized to express low levels of coagulation Factor IX in the first hemophilia B gene therapy clinical trial. However, our experiments in mice demonstrated that the specific activity of muscle-synthesized Factor IX via gene transfer decreased at the high levels of FIX expression by a limited muscle area (Schuettrumpf J. et al., Blood 2005). These results suggest that in vitro and in vivo expression of biologically-active VKCPs outside the liver may be limited by the host cell post-translational modification machinery. Here, we performed a systematic study to determine the expression profiles of the vitamin K cycle and furin endoprotease genes in human liver and muscle, compared to the mouse. We also established these profiles in two hemophilic dogs, given the extensive use of this animal model in gene-based hemophilia therapies. RNA from liver and skeletal muscle was used as a template for reverse transcription and the subsequent relative quantification of the GGCX, VKORc1, NQO1, and FURIN genes by qPCR in each tissue using a housekeeping reporter gene. For this, a variety of housekeeping genes were investigated in all three species to identify ones with similar transcript levels in both liver and muscle tissue. We identified the housekeeping genes HPRT1, beta actin, and 18s rRNA as equivalently expressed in the liver and skeletal muscle of human, mouse, and dog, respectively. The relative mRNA transcript quantification of the vitamin K cycle genes in humans showed that the transcript levels of GGCX were similar in liver and muscle. In contrast, both VKORc1 and NQO1 were under-expressed in muscle vs. liver (69.5 ± 4.9% and 67.8 ± 12.5%, respectively, P<0.01). In the mouse, VKORc1 transcript levels in the muscle were reduced to 73.8 ± 9.9% vs. liver (P<0.05), while GGCX and NQO1 exhibited similar transcript levels in both tissues. In the dog, we observed a dramatic reduction in VKORc1 and GGCX transcript levels in the muscle vs. liver (11.8 ± 4.2% and 29.5 ± 15.8%, respectively, P<0.01). Surprisingly, NQO1 transcript levels were 253.8 ± 156.7% higher in muscle than liver (P<0.05). Lastly, in all three species tested, transcript levels for FURIN were similar in both muscle and liver. Our results indicate that VKORc1, a key enzyme in the vitamin K cycle, is consistently under-expressed in the skeletal muscle of humans as well as in mice and hemophilic dogs. In contrast, FURIN transcripts are similarly abundant in the liver and muscle of all three species tested. These suggest that the vitamin K cycle but not propeptide processing by furin can be a limiting factor in the secretion of biologically active muscle-expressed VKCPs. As a result, our observations provide (1) a plausible explanation for the inverse relationship between specific activity and Factor IX expression levels in mice following Factor IX gene transfer, and (2) further support for the mouse and dog as useful models for therapies that depend on the muscle-derived expression of VKCPs. Disclosures No relevant conflicts of interest to declare.
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Stangler Herodež, Špela, Nastja Stankovič, Boris Zagradišnik, Alenka Erjavec Škerget, and Nadja Kokalj Vokač. "Detection of vkorc1 polymorphism: comparison of polymerase chain reaction/restriction fragment length polymorphism (pcr + rflp) with allele–specific polymerase chain reaction." Acta Medico-Biotechnica 6, no. 2 (November 28, 2021): 47–52. http://dx.doi.org/10.18690/actabiomed.91.
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Purpose: The VKORC1 polymorphism is an important genetic factor affecting warfarin dose requirement. Patients require different warfarin doses in order to achieve the target therapeutic anticoagulation. The aim of our study was to determine the frequency of single nucleotide polymorphisms (SNP) in the VKORC1 gene in the general population, using a simple, rapid, and economical method.
Methods: For genotyping, the restriction fragment length polymorphism (RFLP) of polymerase chain reaction (PCR)–amplified DNA was used and compared to allele– specific polymerase chain reaction. We genotyped 441 DNA samples obtained from the healthy general population in North–Eastern Slovenia. Genotypes for the tested group were evaluated to determine whether the population followed the Hardy–Weinberg equilibrium. The genotypes and allele frequencies were calculated.
Results: The results obtained using the allele–specific polymerase chain reaction were consistent with those obtained using the PCR + RFLP method. The G allele frequency (0.62) was higher than the A allele frequency (0.38) in the general population from North–Eastern Slovenia.
Conclusions: The PCR+RFLP method involved additional manipulation of the PCR products at the expense of analysis time, consumption of reagents and equipment. The allele–specific polymerase chain reaction was a simple and rapid method for the detection of SNP in the VKORC1 gene, and is available in any laboratory with the minimum of equipment and reagents required.
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Kim, Jung Sun, Sak Lee, Jeong Yee, Kyemyung Park, Eun Jeong Jang, Byung Chul Chang, and Hye Sun Gwak. "Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study." Biomedicines 11, no. 8 (August 19, 2023): 2308. http://dx.doi.org/10.3390/biomedicines11082308.
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Warfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable warfarin dose in the Korean population with cardiac valve replacement, using the GWAS approach. This retrospective cohort study was performed from January 1982 to December 2020 at the Severance Cardiovascular Hospital of Yonsei University College of Medicine. GWAS was performed to identify associations between genotypes and the warfarin maintenance dose, by comparing the allele frequency of genetic variants between individuals. Then, the extent of genetic and non-genetic factors on the dose variability was determined by multivariable regression analysis. The study enrolled 214 participants, and the most robust signal cluster was detected on chromosome 16 around VKORC1. Followed by VKORC1, three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) showed an association with stable warfarin dose requirement in univariate analysis. The algorithm was constructed by using multivariable analysis that includes genetic and non-genetic factors, and it could explain 58.5% of the variations in stable warfarin doses. In this variability, VKORC1 rs9934438 and FRAS1 rs4386623 accounted for 33.0% and 9.9%, respectively. This GWAS analysis identified the fact that three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) were associated with stable warfarin doses. Additional research is necessary to validate the results and establish personalized treatment strategies for the Korean population.
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Zotova, I. V., A. G. Nikitin, E. N. Fattakhova, A. N. Brovkin, D. S. Khodyrev, E. Y. Lavrikova, M. Y. Isaeva, A. S. Kosukhina, V. V. Nosikov, and D. A. Zateyshchikov. "THE AFFECT OF INFLUENCE OF GENES' POLYMORPHISMS CYP2C9 AND VKORC1ON THE SAFETY OF THE THERAPY BY WARFARIN." Journal of Clinical Practice 4, no. 4 (December 15, 2013): 3–10. http://dx.doi.org/10.17816/clinpract443-10.
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To study the distribution of alleles and genotypes of polymorphic markers of genes CYP2C9 and VKORC1 of Russian patients who live in Moscow, and in order to assess the influence of genetic factors on warfarin therapy 400 patients have been genotyped. The dosage of warfarin which is required for achievement of INR target values has been different among owners of different geno- types of polymorphic markers of genes CYP2C9 . Meanwhile the highest average dose has been required for genotype *1/*1 and the lowest – for owners of alleles *2 and *3 . For polymorphism G(- 1639)A of the gene VKORC1 the dosage of warfarin which is required for achievement of the INR target values, has been different among owners of different genotypes. The highest average dose has been required for genotype GG, and the lowest – for genotype AA. The results will allow to work out more accurate algorithm of choosing of the initial dose of warfarin depending on the genotypes of polymorphic markers of genes CYP2C9 and VKORC1.
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Li, Dan, Hong Zhu, Zhi-Ying Luo, Yi Chen, Guo-Bao Song, Xin-Ming Zhou, Han Yan, Hong-Hao Zhou, Wei Zhang, and Xi Li. "LRP1 polymorphisms associated with warfarin stable dose in Chinese patients: a stepwise conditional analysis." Pharmacogenomics 21, no. 16 (November 2020): 1169–78. http://dx.doi.org/10.2217/pgs-2020-0004.
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Aim: The aim of this study was to investigate whether variability in warfarin stable dose (WSD) could be influenced by vitamin K-related polymorphisms in patients with heart valve replacement. Patients & methods: Twenty-nine vitamin K-related SNPs in 208 patients who initially took warfarin and achieved WSD were genotyped. Results: After conducting conditional analysis for both VKORC1 -1639G>A and CYP2C9*3, LRP1 rs1800139 and LRP1 rs1800154 were significantly associated with WSD (p = 0.007 and p = 0.015, respectively). Multivariate analysis showed that LRP1 rs1800139 accounted for 5.9% WSD variability. Conclusion: Our results suggest that a novel vitamin K-related gene, LRP1, exerts a relevant influence on WSD, independent of VKORC1 -1639G>A and CYP2C9*3.
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M.R., Zhalbinova, Rakhimova S.E., Andosova S.A., Akilzhanova G.A., Bekbosynova M.S., and Akilzhanova A.R. "ESTIMATION OF THE WARFARIN DOSE IN HEART FAILURE PATIENTS WITH IMPLANTED MECHANICAL CIRCULATORY SUPPORT DEVICE." Наука и здравоохранение, no. 1(25) (February 28, 2023): 59–66. http://dx.doi.org/10.34689/sh.2023.25.1.007.
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Relevance. Left ventricular assist device (LVAD) is an alternative treatment for heart failure (HF) patients which improves patient’s quality of life at their end-stage. Despite to the improvement LVAD is beleaguered with thrombosis/bleeding complications in 70% of HF patients after implantation. An anticoagulant treatment of warfarin is usually prescribed to reduce thrombosis complications. However, due to the incorrect dosage of the treatment thrombosis/ bleeding complications still happen. Warfarin dose could be identified by genetic variants of vitamin K-epoxide reductase complex (VKORC1) and the cytochrome P450-2C9 (CYP2C9) which account for 50% of dose variability. Aim. The aim of our investigation is to identify variability of warfarin dose according to the genotype polymorphisms of genes and their difference from the clinical dosage in HF patients. Materials and methods. The case series study included 98 HF patients (without complications – 74 patients, with complications – 24 patients) with prescribed warfarin treatment after device implantation. Clinical warfarin dosage difference was identified between genotype polymorphisms of rs9923231, rs9934438 in VKORC1 gene. Furthermore, warfarin dosage was calculated according to the genetic test results and compared with clinical dosage. Results. Warfarin dosage according to the clinical protocol between three genotypes of polymorphisms in VKORC1gene showed significant difference. HF patients were prescribed with higher warfarin dosage with wild type genotype polymorphism of rs9934438 in VKORC1 gene than with mutant genotype < 2.5mg (3.88 ± 1.25 vs. 2.44 ± 0.81, p = 0.00005). Conclusion. Genotype-guided warfarin dosing may estimate accurate dose and potentially improve outcomes in LVAD patients. Введение. Вспомогательное механическое устройство левого желудочка (Left ventricular assist device, LVAD) является альтернативным методом лечения пациентов с сердечной недостаточностью (СН), которое улучшает качество жизни пациентов на терминальной стадии. Несмотря на улучшение, LVAD сопровождается тромбозами/кровотечениями у 70% пациентов с СН после имплантации. Антикоагулянтное лечение варфарином обычно назначают для уменьшения осложнений тромбоза. Однако из-за неправильной дозировки лечения осложнения тромбоза/кровотечения все же случаются. Дозу варфарина можно определить по генетическим вариантам комплекса витамин К-эпоксидредуктазы (VKORC1) и цитохрома P450-2C9 (CYP2C9), которые влияет на вариабельности дозы на 50%. Цель. Целью нашего исследования является выявление вариабельности дозы варфарина в зависимости от генетических полиморфизмов генов и их отличия от клинической дозы у больных СН. Материалы и методы. В исследование серии случаев включены 98 пациентов с СН (без осложнений – 74 пациента, с осложнениями – 24 пациента), получавших лечение варфарином после имплантации устройства. Выявлена клиническая разница в дозировке варфарина между полиморфизмами генотипов rs9923231, rs9934438 гена VKORC1. Кроме того, дозировка варфарина рассчитывалась по результатам генетического теста и сравнивалась с клинической дозировкой. Результаты. Дозировка варфарина согласно клиническому протоколу между тремя генотипами полиморфизмов гена VKORC1 показала значительную разницу. Пациентам с СН назначали более высокие дозы варфарина при диком типе полиморфизма rs9934438 гена VKORC1, чем при мутантном генотипе <2,5 мг (3,88 ± 1,25 против 2,44 ± 0,81, p = 0,00005). Выводы. Дозирование варфарина с учетом генотипа может дать точную оценку дозы и потенциально улучшить исходы у пациентов с LVAD. Өзектілігі. Сол жақ қарыншаның көмекші механикалық құрылғысы (Left ventricular assist device, LVAD) жүрек жеткіліксіздігі (ЖЖ) бар науқастарға арналған балама емдеу әдісі болып табылады, ол соңғы сатыдағы пациенттердің өмір сапасын жақсартады. Жақсарғанына қарамастан, 70% ЖЖ пациенттерінде тромбоз/ қан кету асқынулары пайда болады LVAD имплантациясынан кейін. Тромбоздың асқынуын азайту үшін антикоагулянттық емдеу варфаринмен әдетте тағайындалады. Дегенмен, тромбоз/қан кету асқынулары емдеудің дұрыс емес дозасынан туындайды. Дозаның өзгергіштігіне 50%-ға әсер ететін, К витаминінің эпоксид-редуктаза кешенінің (VKORC1) және P450-2C9 цитохромының (CYP2C9) генетикалық нұсқалары арқылы варфариннің дозасын анықтауға болады. Мақсаты. Біздің зерттеуіміздің мақсаты гендік полиморфизмге байланысты варфарин дозасының өзгергіштігін және олардың жүрек жеткіліксіздігі бар науқастардағы клиникалық дозадан айырмашылығын анықтау болып табылады. Материалдар мен әдістер. Жағдайлар сериясына зерттеуге LVAD құрылғысы имплантациясынан кейін варфаринмен емделген 98 ЖЖ пациенттері (асқынулары жоқ – 74 пациент, асқынулары бар - 24 пациент ) қамтылды. Варфарин дозасының клиникалық айырмашылығы VKORC1 генінде полиморфизмдерінің rs9923231 және rs9934438 генотиптерінің арасында анықталды. Сонымен қатар, варфариннің дозасы генетикалық сынақ нәтижелері бойынша есептелді және клиникалық дозамен салыстырылды. Нәтижелер. VKORC1 гендік полиморфизмінің үш генотипі арасындағы варфарин клиникалық дозасы айтарлықтай айырмашылықты көрсетті. ЖЖ бар емделушілер VKORC1 генінің rs9934438 полиморфизмінде, мутантты генотипке қарағанда (<2,5 мг) жабайы типте варфариннің жоғары дозасын қабылдады, (3,88 ± 1,25 қарсы 2,44 ± 0,81, p= 0,00005). Қорытынды. Варфариннің генотипі бойынша дозаның нақты дозасын анықтауға және LVAD пациенттеріндегі нәтижелерді жақсартуы мүмкін.