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Thromb Haemost 2006; 95(02): 205-211
DOI: 10.1160/TH05-06-0446
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin

Manuela Vecsler
1   Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Ronen Loebstein
2   Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
,
Shlomo Almog
2   Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Daniel Kurnik
2   Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
,
Boleslav Goldman
1   Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Hillel Halkin
2   Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Eva Gak
1   Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
› Author Affiliations
Further Information

Publication History

Received 26 June 2005

Accepted after resubmission 08 January 2005

Publication Date:
28 November 2017 (online)

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Summary

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), γ-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G1542C VKORC1 polymorphism was associated with decreased warfarin doses in the heteroand homozygous mutant patients (21% and 50% lower, respectively; p<0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r2= 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G11A CALU mutant allele, required an excep tionally high warfarin dose (20mg/day) and the prevalence of heterozygous 11A allele carriers in the upper 10th dose percentile was significantly higher (0.27 vs. 0.18, p<0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7. 8±1. 5mg/day; n=9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2. 8±0. 3mg/day; n=18; p<0.01). The odds ratio for doses <3mg/day was 5. 9 (1.9–18. 4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.

Keywords

warfarin (coumarin) sensitivity - vitamin K cycle - single nucleotide polymorphisms (SNPs) - combined genotype - pharmacogenetics
 

  • References

  • 1 Dobrzanski S, Duncan SE, Harkiss A. et al. Age and weight as determinants of warfarin requirements. J Clin Hosp Pharm 1983; 08: 75-7.
    PubMedGoogle Scholar
  • 2 Kamali F, Edwards C, Butler TJ. et al. The influence of (R)and (S)-warfarin, vitamin K and vitaminK epoxide upon warfarin anticoagulation. Thromb Haemost 2000; 84: 39-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Absher RK, Moore ME, Parker MH. Patient-specific factors predictive of warfarin dosage requirements. Ann Pharmacother 2002; 36: 1512-7.
    CrossrefPubMedGoogle Scholar
  • 4 Naganuma M, Shiga T, Nishikata K. et al. Role of desethyamiodarone in the anticoagulant effect of concurrent amiodarone and warfarin therapy. J Cardiovasc Pharmacol Ther 2001; 06: 363-7.
    CrossrefPubMedGoogle Scholar
  • 5 Aithal GP, Day CP, Kesteven PJ. et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-9.
    CrossrefPubMedGoogle Scholar
  • 6 Loebstein R, Yonath H, Peleg D. et al. Interindividual variability in sensitivity to warfarin- nature or nurture?. Clin Pharmacol Ther 2001; 70: 159-64.
    CrossrefPubMedGoogle Scholar
  • 7 Scordo MG, Pengo V, Spina E. et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002; 72: 702-10.
    CrossrefPubMedGoogle Scholar
  • 8 Higashi MK, Veenstra DL, Midori LKondo. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-8.
    CrossrefPubMedGoogle Scholar
  • 9 D’Andrea G, D’Ambrosio RL, Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105: 645-9.
    CrossrefPubMedGoogle Scholar
  • 10 Bodin L, Verstuyft C, Tregouet DA. et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005; 106: 135-40.
    CrossrefPubMedGoogle Scholar
  • 11 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-93.
    CrossrefPubMedGoogle Scholar
  • 12 Hirsh J, Dalen J, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
    CrossrefPubMedGoogle Scholar
  • 13 Wallin R, Sane DC, Hutson SM. Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gammacarboxylation system. Thromb Res 2002; 108: 221-6.
    CrossrefPubMedGoogle Scholar
  • 14 Wu SM, Cheung WF, Frazier D. et al. Cloning and expression of the cDNA for human ?-glutamyl carboxylase. Science 1991; 254: 1634-6.
    CrossrefPubMedGoogle Scholar
  • 15 Brenner B, Sanchez-Vega B, Wu SM. et al. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin Kdependent blood coagulation factors. Blood 1998; 92: 4554-9.
    PubMedGoogle Scholar
  • 16 Spronk HM, Farah RA, Buchanan GR. et al. Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 2000; 96: 3650-2.
    PubMedGoogle Scholar
  • 17 Shikata E, Ieiri I, Ishiguro S. et al. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (vitamin K-dependent protein-Factors II, VII, IX, and X, proteins S and C, and g-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004; 103: 2630-5.
    CrossrefPubMedGoogle Scholar
  • 18 Wadelius M, Chen LY, Downes K. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 05: 262-70.
    CrossrefPubMedGoogle Scholar
  • 19 Li T, Chang CY, Jin DY. et al. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541-4.
    CrossrefPubMedGoogle Scholar
  • 20 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-41.
    CrossrefPubMedGoogle Scholar
  • 21 Pelz HJ, Rost S, Hunerberg M. et al. The genetic basis of resistance to anticoagulants in rodents. Genetics 2005; 170: 1839-47.
    CrossrefPubMedGoogle Scholar
  • 22 Cain D, Hutson SM, Wallin R. Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem 1997; 272: 29068-75.
    CrossrefPubMedGoogle Scholar
  • 23 Loebstein R, Vecsler M, Kurnik D. et al. Common genetic variants of microsomal epoxide hydrolase (mEH) affect warfarin dose requirements beyond the effect of CYP2C9. Clin Pharmacol Ther 2005; 77: 365-72.
    CrossrefPubMedGoogle Scholar
  • 24 Wallin R, Hutson SM, Cain D. et al. A molecular mechanism for genetic warfarin resistance in the rat. FASEB J 2001; 15: 2542-4.
    CrossrefPubMedGoogle Scholar
  • 25 Wajih N, Sane DC, Hutson SM. et al. The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J Biol Chem 2004; 279: 25276-83.
    CrossrefPubMedGoogle Scholar
  • 26 Lubetsky A, Dekel-Stern E, Chetrit A. et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999; 81: 396-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Davidson KW, Sadowski JA. Determination of vitamin K compounds in plasma or serum by high-performance liquid chromatography using postcolumn chemical reduction and fluorimetric detection. Methods Enzymol 1997; 284: 408-21.
    PubMedGoogle Scholar
  • 28 Bjornsson TD, Blaschke TF, Meffin PJ. High-pressure liquid chromatographic analysis of drugs in biological fluids I. Warfarin. J Pharm Sci 1977; 66: 142-4.
    CrossrefPubMedGoogle Scholar
  • 29 Harrington DJ, Underwood S, Morse C. et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 23-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Yuan HY, Chen JJ, Lee MT. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-51.
    CrossrefPubMedGoogle Scholar
  • 31 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-33.
    CrossrefPubMedGoogle Scholar
  • 32 Wallin R, Hutson SM. Warfarin and the vitamin K-dependent gamma-carboxylation system. Trends Mol Med 2004; 10: 299-302.
    CrossrefPubMedGoogle Scholar
  • 33 Xie HG, Prasad HC, Kim RB. et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002; 54: 1257-70.
    CrossrefPubMedGoogle Scholar
  • 34 Miyata M, Kudo G, Lee YH. et al. Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7,12-dimethylbenz[a]anthracene. J Biol Chem 1999; 274: 23963-8.
    CrossrefPubMedGoogle Scholar
  • 35 Hassett C, Aicher L, Sidhu JS. et al. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet 1994; 03: 421-8.
    CrossrefPubMedGoogle Scholar
  • 36 To-Figueras J, Gene M, Gomez-Catalan J. et al. Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk. Cancer Lett 2002; 187: 95-101.
    CrossrefPubMedGoogle Scholar
  • 37 Gsur A, Zidek T, Schnattinger K. et al. Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk. Br J Cancer 2003; 89: 702-6.
    CrossrefPubMedGoogle Scholar
  • 38 Wu SM, Stafford DW, Frazier LD. et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood 1997; 89: 4058-62.
    PubMedGoogle Scholar