DOCSLIB.ORG

Vitamin K Epoxide Recycling Polypeptide Vkorc1, a Therapeutic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Vitamin K Epoxide Recycling Polypeptide Vkorc1, a Therapeutic (19) TZZ __T (11) EP 2 272 951 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 9/04 (2006.01) C12N 15/52 (2006.01) 23.07.2014 Bulletin 2014/30 C07K 16/40 (2006.01) G01N 33/50 (2006.01) A01K 67/027 (2006.01) C12N 5/10 (2006.01) (21) Application number: 10011278.8 (22) Date of filing: 12.10.2004 (54) Vitamin k epoxide recycling polypeptide vkorc1, a therapeutic target of coumarin and their derivatives VKCORC1 (vitamin k epoxide recycling polypeptide), ein therapeutisches Ziel für Coumarin und deren Derivate Polypeptide VKCORC1 de recyclage de la vitamine k- epoxide, cible thérapeutique de la coumarine et de ses dérivés (84) Designated Contracting States: (74) Representative: HOFFMANN EITLE AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Patent- und Rechtsanwälte HU IE IT LI LU MC NL PL PT RO SE SI SK TR Arabellastrasse 4 81925 München (DE) (30) Priority: 14.10.2003 US 511041 P (56) References cited: (43) Date of publication of application: EP-A1- 2 189 523 WO-A-00/03015 12.01.2011 Bulletin 2011/02 WO-A2-2005/030039 (62) Document number(s) of the earlier application(s) in • ROST SIMONE ET AL: "Mutations in VKORC1 accordance with Art. 76 EPC: cause warfarin resistance and multiple 10002316.7 / 2 189 523 coagulation factor deficiency type 2.", NATURE. 04790318.2 / 1 673 450 5 FEB 2004, vol. 427, no. 6974, 5 February 2004 (2004-02-05), pages537-541, XP002318816, ISSN: (73) Proprietors: 1476-4687 • Baxter International Inc. • LI TAO ET AL: "Identification of the gene for Deerfield, IL 60015 (US) vitamin K epoxide reductase.", NATURE. 5 FEB • Baxter Healthcare SA 2004, vol. 427, no. 6974, 5 February 2004 8152 Glattpark (Opfikon) (CH) (2004-02-05), pages541-544, XP002318817, ISSN: 1476-4687 (72) Inventors: • DATABASE GENPEPT [Online] NCBI; 25 August • Oldenburg, Johannes 2004 (2004-08-25), ROST ET AL.: "vitamin K 53639 Königswinter (DE) epoxide reductase complex, subunit 1; vitamin • Müller-Reible, Clemens R. K1 epoxide reductase (warfarin-sensitive); 97082 Würzburg (DE) phylloquinone epoxide reductase", • Fregin, Andreas XP002318820, retrieved from NCBI Database 55129 Mainz (DE) accession no. NP_848715 • Strom, Tim-Mathhias 80798 München (DE) • Rost, Simone 97072 Würzburg (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 272 951 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 272 951 B1 • DATABASE EMBL [Online] Last update • OLDENBURG J ET AL: "Congenital deficiency of 22.09.2003 8 February 2001 (2001-02-08), "Mus vitamin K dependent coagulation factors in two musculus 13 days embryo head cDNA, RIKEN families presents as a genetic defect of the full-length enriched library, clone:3110005B16 vitamin K-epoxide-reductase-complex", product:hypothetical protein, full insert THROMBOSIS AND HAEMOSTASIS, vol. 84, no. sequence.", XP002318821, retrieved from EBI 6, December 2000 (2000-12), pages 937-941, accession no. EM_PRO:AK013996 Database XP008043307, ISSN: 0340-6245 accession no. AK013996 • ZIMMERMANN A ET AL: "Biochemical basis of • DATABASE UniProt [Online] 1 June 2001 hereditary resistance to warfarin in the rat", (2001-06-01), "Mus musculus 13 days embryo BIOCHEMICAL PHARMACOLOGY 1974, vol. 23, head cDNA, RIKEN full-length enriched library, no. 6, 1974, pages 1033-1040, XP002318819, clone:3110005B16 product:hypothetical protein, fullinsert sequence (Vitamin K epoxide reductase complex, subunit 1) (Mus musculus adult male kidney cDNA, RIKEN full- length enriched library, clone:0610033K05 product:hypotheti", XP002318822, retrieved from EBI accession no. UNIPROT:Q9CRC0 Database accession no. Q9CRC0 • FREGIN ANDREAS ET AL: "Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16", BLOOD, vol. 100, no. 9, 1 November 2002 (2002-11-01), pages 3229-3232, XP002318818, ISSN: 0006-4971 2 EP 2 272 951 B1 Description Field of the Invention 5 [0001] The invention relates to a method for gamma-carboxylating a vitamin K-dependent polypeptide in a host cell comprising introducing into said host cell a nucleic acid that encodes VKORC1 in a manner that the nucleic acid encoding VKORC1 is recombinantly expressed in said cell. Further, the present invention relates to a use of a recombinant VKORC1 nucleic acid for gamma-carboxylating a vitamin K-dependent polypeptide in a host cell. 10 Background of the invention [0002] Repression of untimely blood coagulation is the therapeutic option of choice for acute treatment and long-term prevention of thrombolic events. Among the anti-coagulants coumarins are widely used for the prevention of thrombosis such as in patients immobilized after surgery, patients having a chronic heart failure, patients having atherosclerotic 15 vascular disease, patients having a malignancy, and patients that are pregnant. Moreover, coumarins are the most widely used oral anticoagulants for the treatment and prophylaxis of thrombosis [Suttie, 1987]. Coumarins are typically derivatives of 6-hydroxycoumarin, such as 3-(acetonylbenzyl)-4- hydroxycoumarin (COUMADIN ®). [0003] The coumarins target the blood coagulation cascade indirectly by inhibition of the vitamin K cycle. [0004] Vitamin K is an essential cofactor for the post-translational activation by gamma-carboxylation of a group of 20 regulatory proteins, the Gla-proteins. In several metabolic pathways, some key proteins require carboxylation for proper function. The blood coagulation cascade is the best-studied example. Here, the procoagulant factors II, VII, IX and X, and the anticoagulant factors protein C, protein S, protein Z are dependent on gamma-carboxylation. This post-trans- lational modification enables the attachment of the modified proteins - in the presence of calcium - to phospholipid- bilayer membranes which is an essential step in the activation of blood coagulation [Sperling et al., 1978][Esmon et al., 25 1975]. Other proteins requiring gamma-carboxylation are the matrix gla protein and osteocalcin, both regulators of bone metabolism [Price, 1988] and the "growth arrest specific gene", a signal transduction protein of the cell cycle[Manfioletti et al., 1993][Stitt et al., 1995]. [0005] During gamma-carboxylation, a carboxyl group is introduced into glutamate residues of the target proteins by the enzyme gamma-glutamyl carboxylase (GGCX) in liver microsomes [Furie & Furie, 1988][Suttie, 1987]. The reaction 30 requires as a cofactor stoichiometric amounts of reduced vitamin K1 hydroquinone (vitamin K1H2) which is oxidized to vitamin K-2,3 epoxide[Cain et al., 1997]. The regeneration of the active cofactor is mediated by a multi-protein complex termed vitamin K-2,3-epoxide reductase (VKOR) [Wallin & Martin, 1985]. The same complex is targeted by the coumarin- type poisons used in rodent pest control. This "vitamin K cycle" has been characterized biochemically in great detail but the molecular components have not yet been purified to homogeneity [Guenthner et al., 19981]. Moreover, the molecular 35 nature of coumarin activity and the molecules interacting with coumarins are still elusive. [0006] It is generally appreciated in the art that although largely effective, there are a number of limitations to the use of coumarins. First of all; there are humans that are inert to coumarin treatment. The term warfarin resistance (WR) is used for individuals who maintain normal clotting factor activities despite oral anticoagulation by coumarins (OMIM Access. No. 122700). Autosomal dominant transmission has been observed in several pedigrees [O’Reilly et al., 40 1964][O’Reilly, 1970]. Combined deficiency of all vitamin K dependent clotting factors (VKCFD) is a very rare bleeding disorder in humans of autosomal recessive inheritance with 14 cases described as yet[McMillan & Roberts, 1966][Fischer, 1966][Johnson et al., 1980][Goldsmith et al., 1982][Vicente et al., 1984][Ekelund et al., 1986][Pauli et al., 1987][Leonard, 1988][Pechlaner et al., 1992][Boneh & Bar-Ziv, 1996][Brenner et al., 1998][Spronk et al., 2000][Oldenburg et al., 2000]. Clinical symptoms of the disease include episodes of perinatal intracerebral hemorrhage sometimes with fatal outcome. 45 The bleeding tendency is usually completely reversed by oral administration of vitamin K. Additional symptoms in new- borns can resemble warfarin embryopathy with nasal and distal phalangeal hypoplasia and premature calcification of epiphyses[Pauli et al., 1987]. The disease may result either from a defective resorption/transport of vitamin K to the liver [Prentice, 1985] or from mutations in one of the genes involved in gamma-carboxylation. In subtype 1 (VKCFD1, OMIM # 277450), mutations in the GGCX gene on chromosome 2p12 result in insufficient carboxylation of clotting factors 50 [Brenner et al., 1998][Spronk et al., 2000 ]. There has been described a linkage of two kindreds with familial multiple coagulation factor deficiency (FMFD, now re-named: VKCFD2, OMIM # 607473) to a 20 Mb interval of the pericentric region of chromosome 16p12-q21 [Fregin et al., 2002]. Patients with VKCFD2 showed significantly increased serum levels of vitamin K epoxide, thus suggesting a defect in one of the subunits of the VKOR complex. Taken together, there is evidence that there are patients that display warfarin resistance. As a result, there is a need to identify novel coumarins 55 derivatives that are effective anticoagulants for treating these patients, and methods for identifying these coumarin derivatives. [0007] The use of coumarins is associated with a risk of spontaneous bleedings, with a significant mortality rate. Moreover, the prediction of the accurate coumarin maintenance dose is difficult. In the absence of the target molecule 3 EP 2 272 951 B1 which coumarin exerts an effect on, the treatment regimen has to be established, on a patient-by-patient basis.
Load more

Recommended publications
  • Association of VKORC1 and CYP2C9 Polymorphisms with Warfarin Dose Requirements in Japanese Patients
    J Hum Genet (2006) 51:249–253 DOI 10.1007/s10038-005-0354-5 ORIGINAL ARTICLE Taisei Mushiroda Æ Yozo Ohnishi Æ Susumu Saito Atsushi Takahashi Æ Yuka Kikuchi Æ Shigeru Saito Hideki Shimomura Æ Yasuhiko Wanibuchi Takao Suzuki Æ Naoyuki Kamatani Æ Yusuke Nakamura Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients Received: 11 October 2005 / Accepted: 28 November 2005 / Published online: 24 January 2006 Ó The Japan Society of Human Genetics and Springer-Verlag 2006 Abstract Warfarin is the most commonly used oral homozygous for the major allele (2.5 mg/day; anticoagulant for treatment of thromboembolism, but P=5.1·10À11 in the case of intron 1À136T>C SNP). adjustment of the dose appropriate to each patient is not We then genotyped the CYP2C9 gene for the Japanese so easy because of the large inter-individual variation in common genetic variant, CYP2C9*3 and, based on the dose requirement. We analyzed single nucleotide poly- genotype of these two genes, classified patients into three morphism (SNP) genotypes of the VKORC1 and categories, which we call ‘‘warfarin-responsive index.’’ CYP2C9 genes using DNA from 828 Japanese patients The median warfarin daily dose varied significantly in treated with warfarin, and investigated association be- this classification according to the warfarin-responsive tween SNP genotype and warfarin-maintenance dose. index (2.0 mg/day for index 0 group, 2.5 mg/day for Five SNPs in VKORC1,5¢ flankingÀ1413A>G, intron index 1 group, and 3.5 mg/day for index 2 group; 1À136T>C, intron 2+124C>G, intron 2+837T>C P=4.4·10À13).
    [Show full text]
  • Adaptative Evolution of the Vkorc1 Gene in Mus Musculus Domesticus
    Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides Joffrey Goulois, Véronique Lambert, Lionel Legros, Etienne Benoit, Virginie Lattard To cite this version: Joffrey Goulois, Véronique Lambert, Lionel Legros, Etienne Benoit, Virginie Lattard. Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides. Ecology and Evolution, Wiley Open Access, 2017, 7 (8), pp.2767-2776. 10.1002/ece3.2829. hal-01603961 HAL Id: hal-01603961 https://hal.archives-ouvertes.fr/hal-01603961 Submitted on 26 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - ShareAlike| 4.0 International License Received: 27 July 2016 | Revised: 15 January 2017 | Accepted: 28 January 2017 DOI: 10.1002/ece3.2829 ORIGINAL RESEARCH Adaptative evolution of the Vkorc1 gene in Mus musculus domesticus is influenced by the selective pressure of anticoagulant rodenticides Joffrey Goulois1,2 | Véronique Lambert1 | Lionel Legros2 | Etienne Benoit1 | Virginie Lattard1 1USC 1233 RS2GP, VetAgro Sup, INRA, Univ Lyon, F-69280, MARCY L’ETOILE, France Abstract 2Liphatech, Bonnel, Pont du Casse, France Anticoagulant rodenticides are commonly used to control rodent pests worldwide.
    [Show full text]
  • Positive Selection in the Chromosome 16 VKORC1 Genomic Region Has Contributed to the Variability of Anticoagulant Response in Humans
    Positive Selection in the Chromosome 16 VKORC1 Genomic Region Has Contributed to the Variability of Anticoagulant Response in Humans Blandine Patillon1,2*., Pierre Luisi3.,He´le`ne Blanche´ 4, Etienne Patin5, Howard M. Cann4, Emmanuelle Ge´nin1", Audrey Sabbagh6" 1 Inserm UMRS-946, Genetic Variability and Human Diseases, Institut Universitaire d’He´matologie, Universite´ Paris Diderot, Paris, France, 2 Universite´ Paris Sud, Kremlin- Biceˆtre, France, 3 Institute of Evolutionary Biology, CEXS-UPF-PRBB, Catalonia, Barcelona, Spain, 4 Fondation Jean-Dausset-CEPH, Paris, France, 5 Human Evolutionary Genetics, CNRS URA3012, Institut Pasteur, Paris, France, 6 UMR IRD 216, Universite´ Paris Descartes, Paris, France Abstract VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area.
    [Show full text]
  • Prevalence​Of​VKORC1​Single​Nucleotide​Polymorphism​(SNP)
    113 Original​Article Prevalence​of​VKORC1​Single​Nucleotide​Polymorphism​(SNP)​–​1639​ in​Thai​Adult​Patients​Who​Have​INR​More​Than​4​from​Warfarin Rawisut​Deoisares​and​Ponlapat​Rojnuckarin Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital Abstract : Background : Previous studies showed that VKORC1 -1639 SNP genotype AA was more common in Asian compared with Caucasian population and associated with lower warfarin dose requirement. We hypothesized that this genetically-determined warfarin sensitivity may predispose the patients with this genotype to warfarin overdosage. Method : A descriptive study was conducted in adult patients taking warfarin with INR more than 4 at King Chulalongkorn Memorial Hospital. The VKORC1 -1639 genotyping in these cases was performed. Results : There were a total of 44 cases of warfarin overdose. The median age was 66 yr, range 21-90 yr, and 15 patients (34%) were male. The numbers (%) of VKORC1 -1639 genotype AA, AG and GG were 26 (59.1%), 16 (36.4%) and 2 (4.5%), respectively. This prevalence was similar to general Thai population and thromboembolic patients receiving warfarin. Conclusion : Our result implies that VKORC1 -1639 polymorphism is not a strong risk factor for warfarin overdose. Key Words : l Warfarin l Overdosage l VKORC1 l Single nucleotide polymorphism J Hematol Transfus Med 2010;20:113-8. Introduction Vitamin K is the cofactor of hepatic gamma carboxylation. Since 1954, warfain has been used worldwide as an After the reaction, vitamin K is transformed into an anticoagulant for treatment or prophylaxis of venous oxidized from that is inactive. VKORC1 can reduce the thromboembolism.1 Warfarin has good oral bioavailability.
    [Show full text]
  • Genotypes of Patients with Vitamin K Dependent Factors Deficiency
    Genotypes of patients with Vitamin K dependent factors deficiency Gene Mutation Location Type Genotype Origin VKDF** VKDF** Comments Reference Activity Antigen % % GGCX IVS1 del 14 bp Intron 1 Undefined Hom 9-30 1 GGCX IVS2+1 G>T Intron 2 Splicing Comp Hispanic 2-4 2 IVS11+3 A>G Intron Splicing het 11 GGCX IVS2-1 G>T Intron 2 Splicing Comp Germany 21-42 3 Arg485Pro* Exon 11 Missense het GGCX Trp157Arg Exon 4 Missense Comp Tunis 5-9 60-73 Expression 4 Thr591Lys and Exon 13 Missense het Expression Asp31Asn Expression indicated polymorphism GGCX Leu394Arg Exon 9 Missense Hom Arab 2-8 10-57 Expression 5,6,7 GGCX His 404Pro Exon 9 Missense Comp Germany 13-54 8 Arg485Pro* Exon 11 Missense het GGCX Trp501Ser* Exon 11 Missense Hom Lebanon 1-6 Expression 9,10 GGCX Trp501Ser* Exon 11 Missense Hom Lebanon 9-35 11 VKORC1 Arg98Trp* Exon 3 Missense Hom Lebanon 20-60 12,13 VKORC1 Arg98Trp* Exon 3 Missense Hom Germany 20-60 12,13 VKORC1 Arg98Trp* Exon 3 Missense Hom Italy 8-26 35-100 14 Nucleotide numbers of GGCX are based on the Genebank file NM_000821 using the A (nt 29) of the ATG initiation methionine as +1. Nucleotide numbers of VKORC1 are based on the Genebank file AY423044 using the A (nt 1) of the ATG initiation methionine as +1. *A mutation that was identified in more than 1 family. **VKDF are prothrombin and factors VII, IX and X REFERENCES 1. Thomas A, Stirling D: Four factor deficiency. Blood Coagul Fibrinolysis Suppl1:S55, 2003.
    [Show full text]
  • ARGENTINA) Espinosa M.B.¹
    27 Journal of Basic & A pplied Genetic s EFFICACY OF ANTICOAGULANT DRUGS AS RODENTICIDES AND GENETIC VARIATION ON Vkorc1 OF Mus musculus FROM BUENOS AIRES PROVINCE (ARGENTINA) Espinosa M.B.¹ ¹Instituto de Investigación en Biociencias Agrícolas y Ambientales(INBA). Avda. San Martín 4453, C1417DSQ. Ciudad Autónoma de Buenos Aires, Argentina. [email protected] ABSTRACT The relationship between anticoagulant rodenticides and the gene for vitamin K epoxide reductase has been extensively studied The significance of mutations in Vkorc1 on the degree of response to anticoagulants is controversial. The implication of the VKORC1 function in pest control drives the attention to a wide range of factors that may be influencing the resistance to rodenticides, an issue that will be discussed in this article. Anticoagulants are used as rodenticides as well as to improve human health. The interactions between VKORC1 and CYP4F18 (cytochrome P450) are complex. It is likely that the coagulation response may be due to a diverse expression of the Vkorc1 gene and its interaction with the expression of Cyp4f18, and to the polymorphisms present in both genes. We analyzed the presence of polymorphisms (especially the presence of mutations that produce substitutions of Tyr139Cys and Leu128Ser) in Vkorc1 of the genome of Mus musculus belonging to local wild populations living in farms. The animals studied were from areas in which rodenticide anticoagulants (ej. bromadiolone) are commonly used as pest control. None of the studied mice showed any signs of anticoagulant resistance-related mutations in the Vkorc1 gene. This study will enable a proper selection of the rodenticide method for pest control in local areas.
    [Show full text]
  • The Mouse Universal Genotyping Array: from Substrains to Subspecies
    G3: Genes|Genomes|Genetics Early Online, published on December 18, 2015 as doi:10.1534/g3.115.022087 INVESTIGATIONS The Mouse Universal Genotyping Array: from substrains to subspecies Andrew P Morgan∗, †, 1, Chen-Ping Fu‡, 1, Chia-Yu Kao‡, Catherine E Welsh§, John P Didion∗,†, Liran Yadgary∗,†, Leeanna Hyacinth∗,†, Martin T Ferris∗,†, Timothy A Bell∗,†, Darla R Miller∗,†, Paola Giusti-Rodriguez∗,†, Randal J Nonneman∗,†, Kevin D Cook∗,†, Jason K Whitmire∗,†, Lisa E Gralinski∗∗,†, Mark Keller††, Alan D Attie††, Gary A Churchill‡‡, Petko Petkov‡‡, Patrick F Sullivan∗, †, §§, Jennifer R Brennan∗ ∗ ∗, Leonard McMillan‡ and Fernando Pardo-Manuel de Villena∗,† ∗Department of Genetics, University of North Carolina, Chapel Hill, NC, †Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, ‡Department of Computer Science, University of North Carolina, Chapel Hill, NC, §Department of Mathematics and Computer Science, Rhodes College, Memphis, TN, ∗∗Department of Epidemiology, University of North Carolina, Chapel Hill, NC, ††Department of Biochemistry, University of Wisconsin, Madison, WI, ‡‡The Jackson Laboratory, Bar Harbor, ME, §§Department of Psychiatry, University of North Carolina, Chapel Hill, NC, ∗ ∗ ∗Mutant Mouse Resource and Research Center, University of North Carolina, Chapel Hill, NC, 1These authors contributed equally. ABSTRACT Genotyping microarrays are an important resource for genetic mapping, population genetics KEYWORDS and monitoring of the genetic integrity of laboratory stocks. We have developed the third generation of microarrays the Mouse Universal Genotyping Array (MUGA) series, GigaMUGA, a 143,259-probe Illumina Infinium II genetic mapping array for the house mouse (Mus musculus). The bulk of the content of GigaMUGA is optimized for genetic inbred strains mapping in the Collaborative Cross and Diversity Outbred populations and for substrain-level identification ..
    [Show full text]
  • Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients During the Initiation Therapy
    G C A T T A C G G C A T genes Article Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy Laith N. AL-Eitan 1,2,* , Ayah Y. Almasri 1 and Rame H. Khasawneh 3 1 Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] 2 Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan 3 Department of Hematopathology, King Hussein Medical Center (KHMC), Jordan Royal Medical Services (RMS), Amman 11118, Jordan; [email protected] * Correspondence: [email protected]; Tel.: +962-2-7201000 (ext. 23464); Fax: +962-2-7201071 Received: 15 October 2018; Accepted: 21 November 2018; Published: 27 November 2018 Abstract: 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.
    [Show full text]
  • Interspecific Introgressive Origin of Genomic Diversity in the House
    Interspecific Introgressive Origin of Genomic Diversity in the House Mouse Kevin J. Liu ∗, Ethan Steinberg y, Alexander Yozzo y , Ying Song z, Michael H. Kohn z , and Luay Nakhleh y z ∗Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824 (Research was performed while KJL was at Rice University),yDepartment of Computer Science, Rice University, Houston, TX 77005, and zBiosciences, Rice University, Houston, TX 77005 Submitted to Proceedings of the National Academy of Sciences of the United States of America We report on a genome-wide scan for introgression in the house trogressive descent origins of the mouse genome were hidden mouse (Mus musculus domesticus) involving the Algerian mouse due to data post-processing that masked introgressed genomic (Mus spretus), using samples from the ranges of sympatry and al- regions as missing data. In another study reporting whole- lopatry in Africa and Europe. Our analysis reveals wide variability genome sequencing of 17 classical lab strains [5], M. spretus in introgression signatures along the genomes, as well as across the was used as an outgroup for phylogenetic analysis. The au- samples. We find that fewer than half of the autosomes in each genome harbor all detectable introgression, while the X chromosome thors were surprised to find that 12.1% of loci failed to place has none. Further, European mice carry more M. spretus alleles than M. spretus as an outgroup to the M. musculus clade. The au- the sympatric African ones. Using the length distribution and shar- thors concluded that M. spretus was not a reliable outgroup, ing patterns of introgressed genomic tracts across the samples, we but did not pursue their observation further.
    [Show full text]
  • The Genetic Basis of Resistance to Anticoagulants in Rodents
    Genetics: Published Articles Ahead of Print, published on May 6, 2005 as 10.1534/genetics.104.040360 The genetic basis of resistance to anticoagulants in rodents Hans-Joachim Pelz*, Simone Rost†, Mirja Hünerberg†, Andreas Fregin†, Ann-Charlotte Heiberg‡, Kristof Baert§, Alan D. MacNicoll#, Colin V. Prescott$, Anne-Sophie Walker&, Johannes Oldenburg@ † and Clemens R. Müller . * Biologische Bundesanstalt für Land- und Forstwirtschaft, Institut für Nematologie und Wirbeltierkunde, 48161 Münster, Germany; † Institut für Humangenetik, Universität Würzburg, Biozentrum, 97074 Würzburg, Germany; ‡ Danish Pest Infestation Laboratory, Danish Institute of Agricultural Sciences, DK-2800 Kgs. Lyngby, Denmark; § Institute for Forestry and Game Management, 9500 Geraardsbergen, Belgium; # Central Science Laboratory, Defra, Sand Hutton, York, YO41 1LZ, UK; $ School of Animal and Microbial Sciences, The University of Reading, Whiteknights, Reading, RG6 6AJ, UK; & Institut National de la Recherche Agronomique (INRA), Unité de Phytopharmacie et Médiateurs Chimiques, 78026 Versailles, France; @ Institut für Transfusionsmedizin und Immunhämatologie, DRK Blutspendedienst Baden- Württemberg - Hessen, 60526 Frankfurt/M, Germany. H.J.P. and S.R. contributed equally to this study. 1/30 Running title: Genetic basis of warfarin resistance Key words: Warfarin resistance, Vitamin K metabolism, VKOR, rodent pest control, blood coagulation Reprints: Clemens R. Mueller, Institut für Humangenetik, Universität Würzburg, Biozentrum, Am Hubland, 97074 Würzburg, Germany; Phone: +49-931-888-4063 Fax: +49-931-888-4069 e-mail: [email protected] 2/30 ABSTRACT Anticoagulant compounds, ie derivatives of either 4-hydroxycoumarin (eg warfarin, bromadiolone) or indane-1,3-dione (eg diphacinone, chlorophacinone) have been in world-wide use as rodenticides for more than 50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR).
    [Show full text]
  • VKORC1 Gene Vitamin K Epoxide Reductase Complex Subunit 1
    VKORC1 gene vitamin K epoxide reductase complex subunit 1 Normal Function The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme is made primarily in the liver. It spans the membrane of a cellular structure called the endoplasmic reticulum, which is involved with protein processing and transport. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Specifically, the VKORC1 enzyme converts one form of vitamin K into a different form of vitamin K that assists in activating clotting proteins. Health Conditions Related to Genetic Changes Warfarin resistance Multiple variations (polymorphisms) in the VKORC1 gene have been associated with warfarin resistance, a condition in which individuals require higher doses of the drug warfarin than are usually prescribed. Warfarin is an anticoagulant, which means that it thins the blood and prevents blood clots from forming. It acts by attaching (binding) to the VKORC1 enzyme and blocking (inhibiting) the activation of the clotting proteins. The most common VKORC1 gene polymorphism in people with warfarin resistance changes a single protein building block (amino acid) in the VKORC1 enzyme. Specifically, the amino acid aspartic acid is replaced with the amino acid tyrosine at position 36 (written as Asp36Tyr or D36Y). This polymorphism leads to the formation of a VKORC1 enzyme with a decreased ability to bind to warfarin. As a result, a higher dose of warfarin is needed to inhibit the VKORC1 enzyme and stop the clotting process. If people with warfarin resistance require anticoagulant treatment and take the average warfarin dose (or less), they will remain at risk of developing a potentially harmful blood clot.
    [Show full text]
  • Clinical Pharmacogenetics Implementation Consortium Guidelines for Cyp2c9and VKORC1 Genotypes and Warfarin Dosing
    nature publishing group TRANSLATION Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing JA Johnson1, L Gong2, M Whirl-Carrillo2, BF Gage3, SA Scott4, CM Stein5, JL Anderson6, SE Kimmel7,8,9, MTM Lee10, M Pirmohamed11, M Wadelius12, TE Klein2 and RB Altman2,13 Warfarin is a widely used anticoagulant with a narrow thera- among the adverse events most frequently reported to the US peutic index and large interpatient variability in the dose Food and Drug Administration (FDA) and one of the most com- required to achieve target anticoagulation. Common genetic mon reasons for emergency room visits.6 variants in the cytochrome P450-2C9 (CYP2C9) and vitamin Warfarin is often dosed empirically: an initial dose is K–epoxide reductase complex (VKORC1) enzymes, in addi- prescribed, typically followed by at least weekly measurement tion to known nongenetic factors, account for ~50% of war- of the INR and subsequent dose adjustment. The initial dose farin dose variability. The purpose of this article is to assist is often based on population averages (e.g., 3–5 mg/day), but in the interpretation and use of CYP2C9 and VKORC1 geno- stable doses to achieve an INR of 2–3 can range from 1–20 mg/ type data for estimating therapeutic warfarin dose to achieve day. The iterative process to define the appropriate dose can an INR of 2–3, should genotype results be available to the take weeks to months, and during this period patients are at clinician. The Clinical Pharmacogenetics Implementation increased risk of over- or under-anticoagulation and thus at Consortium (CPIC) of the National Institutes of Health risk of thromboembolism or bleeding.
    [Show full text]