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Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype-dependent influence of dietary vitamin K intake

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Abstract

Warfarin is the most widely prescribed oral anticoagulant, but large interindividual variations exist in the dose required to achieve comparable therapeutic effects. Several clinical and genetic variables have been identified that influence warfarin dosing. However, interactions between genotype and nutrition remain uncertain in terms of dietary vitamin K intake. To investigate genotype–nutrient interactions in warfarin anticoagulation therapy, 202 consecutive outpatients (M/F = 142/60, mean age, 69 years) undergoing treatment with warfarin were enrolled. Prevalent single nucleotide polymorphisms in VKORC1 and CYP2C9 were genotyped, and dietary vitamin K intake during the week preceding the blood sampling was quantitatively estimated by a dietitian-assisted questionnaire. Patients were classified according to low, medium, or high vitamin K intake. The mean daily warfarin dose in subjects with a VKORC1-1639 A/A genotype was significantly smaller than that with a -1639A/G genotype (2.74 vs. 3.91 mg/day, respectively, p < 0.0001). Dose requirements did not differ between subjects with a CYP2C9 *1/*3 genotype versus a CYP2C9 *1/*1 genotype. In subjects with a variant VKORC1-1639 G allele, the mean daily warfarin dose was significantly attenuated by low vitamin K intake compared with medium and high intake after adjustment for covariates (3.4 vs. 5.0 vs. 4.0 mg/day, respectively, p = 0.028). No such genotype effects were observed in homozygous patients for the VKORC1-1639 A allele. The results of the present study suggest that the capacity of dietary vitamin K intake to influence warfarin dose requirements during anticoagulation therapy is VKORC1 genotype-dependent, at least in part.

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References

  1. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329:15–19

    Article  PubMed Central  PubMed  Google Scholar 

  2. Wester K, Jonsson AK, Spigset O, Druid H, Hägg S (2008) Incidence of fatal adverse drug reactions: a population based study. Br J Clin Pharmacol 65:573–579

    Article  PubMed Central  PubMed  Google Scholar 

  3. Wu AH (2007) Use of genetic and nongenetic factors in warfarin dosing algorithms. Pharmacogenomics 8:851–861

    Article  CAS  PubMed  Google Scholar 

  4. Crowther MA (2003) Oral anticoagulant initiation: rationale for the use of warfarin dosing nomograms. Semin Vasc Med 3:255–260

    Article  PubMed  Google Scholar 

  5. Wadelius M, Pirmohamed M (2007) Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 7:99–111

    Article  CAS  PubMed  Google Scholar 

  6. Ashley EA, Hershberger RE, Caleshu C, Ellinor PT, Garcia JG, Herrington DM, Ho CY, Johnson JA, Kittner SJ, Macrae CA, Mudd-Martin G, Rader DJ, Roden DM, Scholes D, Sellke FW et al (2012) Genetics and cardiovascular disease: a policy statement from the American Heart Association. Circulation 126:142–157

    Article  PubMed Central  PubMed  Google Scholar 

  7. Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Mansfield JW, Robinson M, Barton S, Brunisholz K, Mower CP, Huntinghouse JA, Rollo JS, Siler D, Bair TL, Knight S, Muhlestein JB, Carlquist JF (2012) A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 125:1997–2005

    Article  CAS  PubMed  Google Scholar 

  8. Kurnik D, Loebstein R, Rabinovitz H, Austerweil N, Halkin H, Almog S (2004) Over-the-counter vitamin K1-containing multivitamin supplements disrupt warfarin anticoagulation in vitamin K1-depleted patients: a prospective, controlled trial. Thromb Haemost 92:1018–1024

    CAS  PubMed  Google Scholar 

  9. Franco V, Polanczyk CA, Clausell N, Rohde LE (2004) Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 116:651–656

    Article  CAS  PubMed  Google Scholar 

  10. Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E, Vermeer C (2004) Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose response relationships in healthy subjects. Blood 104:1682–1689

    Google Scholar 

  11. de Assis MC, Rabelo ER, Ávila CW, Polanczyk CA, Rohde LE (2009) Improved oral anticoagulation after a dietary vitamin K-guided strategy: a randomized controlled trial. Circulation 120:1115–1122

    Article  PubMed  Google Scholar 

  12. Aomori T, Yamamoto K, Oguchi-Katayama A, Kawai Y, Ishidao T, Mitani Y, Kogo Y, Lezhava A, Fujita Y, Obayashi K, Nakamura K, Kohnke H, Wadelius M, Ekström L, Skogastierna C et al (2009) Rapid single-nucleotide polymorphism detection of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genes for the warfarin dose adjustment by the SMart-amplification process version 2. Clin Chem 55:804–812

    Article  CAS  PubMed  Google Scholar 

  13. Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, Hasegawa A, Yamamoto K, Horiuchi R (2006) VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 80:169–178

    Article  CAS  PubMed  Google Scholar 

  14. Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Saito S, Shimomura H, Wanibuchi Y, Suzuki T, Kamatani N, Nakamura Y (2006) Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet 51:249–253

    Article  CAS  PubMed  Google Scholar 

  15. Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, Otsuki T, Okayama A, Minematsu K, Naritomi H, Honda S, Tomoike H, Miyata T (2007) Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 120:181–186

    Article  CAS  PubMed  Google Scholar 

  16. Yoshizawa M, Hayashi H, Tashiro Y, Sakawa S, Moriwaki H, Akimoto T, Doi O, Kimura M, Kawarasaki Y, Inoue K, Itoh K (2009) Effect of VKORC1-1639 G > A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res 124:161–166

    Article  CAS  PubMed  Google Scholar 

  17. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541

    Article  CAS  PubMed  Google Scholar 

  18. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544

    Article  CAS  PubMed  Google Scholar 

  19. The International Warfarin Pharmacogenetics Consortium (2009) Estimation of the Warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764

    Article  PubMed Central  Google Scholar 

  20. Epstein RS, Moyer TP, Aubert RE, O’Kane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR (2010) Warfarin genotyping reduces hospitalization rates. Results from the MM-WES (Medco–Mayo Warfarin Effectiveness Study). J Am Coll Cardiol 55:2804–2812

    Article  CAS  PubMed  Google Scholar 

  21. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293

    Article  CAS  PubMed  Google Scholar 

  22. Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and interethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751

    Article  CAS  PubMed  Google Scholar 

  23. Sconce EA, Avery PJ, Wynne HA, Kamali F (2008) Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study. J Thromb Haemost 6:1226–1228

    Article  CAS  PubMed  Google Scholar 

  24. Corella D, Ordovas JM (2009) Nutrigenomics in cardiovascular medicine. Circ Cardiovasc Genet 2:637–651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Sconce E, Avery P, Wynne H, Kamali F (2007) Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 109:2419–2423

    Article  CAS  PubMed  Google Scholar 

  26. Lurie Y, Loebstein R, Kurnik D, Almog S, Halkin H (2010) Warfarin and vitamin K intake in the era of pharmacogenetics. Br J Clin Pharmacol 70:164–170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by research grants to K.K as follows: a Grant for Collaborative Research from Kanazawa Medical University (C2011–3), Grants for Project Research from the High-Tech Research Center of Kanazawa Medical University (2010–2012, 2011–2012), and a Grant-in-Aid for Scientific Research (Grant Number 25460661) from the Japan Society for the Promotion of Science (JSPS).

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Authors and Affiliations

  1. Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, 920-0293, Japan

    Ryuhei Saito, Kenji Takeda, Hirofumi Aoki, Kosuke Fujibayashi, Minoru Wakasa, Atsushi Motoyama, Mizuho Iwadare, Ryoko Ishida, Nakaba Fujioka, Taketsugu Tsuchiya, Hironobu Akao, Yasuyuki Kawai, Michihiko Kitayama & Kouji Kajinami

  2. Dietary Department, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, 920-0293, Japan

    Kayo Yamamoto & Akihiko Nakagawa

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  1. Ryuhei Saito
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Correspondence to Kouji Kajinami.

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Saito, R., Takeda, K., Yamamoto, K. et al. Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype-dependent influence of dietary vitamin K intake. J Thromb Thrombolysis 38, 105–114 (2014). https://doi.org/10.1007/s11239-013-0978-9

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  • DOI: https://doi.org/10.1007/s11239-013-0978-9

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