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Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves

Abstract

Interindividual variability in stable warfarin doses is largely attributed to VKORC1 and CYP2C9 variants. On the basis of a recent finding of the role of GATA4 in control of CYP2C9 expression, we tested a possible effect of GATA4 genotypes on variability in warfarin response using 201 Korean patients with prosthetic cardiac valves. Two single-nucleotide polymorphisms (SNPs), rs2645400 (G>T) and rs4841588 (G>T), were significantly associated with stable warfarin doses in patients carrying CYP2C9 wild-type homozygotes; homozygote carriers of these two SNPs required higher doses than those with other genotypes (5.94±1.73 versus 5.34±1.88 mg, P=0.026; 5.94±1.66 versus 5.37±1.92, P=0.036, respectively). Multivariate analysis showed that two GATA4 combinations, rs867858 (G>T)/rs10090884 (A>C) and rs2645400 (G>T)/rs4841588 (G>T), increased contribution to the overall warfarin dose variability from 36.4 to 40.9%. This study revealed that GATA4 can be predictive of stable warfarin dose and extended warfarin pharmacogenetics further to the regulation of CYP2C9 expression.

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References

  1. Penning-van Beest FJA, Geleijnse JM, van Meegen E, Vermeer C, Rosendaal FR, Stricker BHC . Lifestyle and diet as risk factors for overanticoagulation. J Clin Epidemiol 2002; 55: 411–417.

    Article  Google Scholar 

  2. Carlquist JF, Horne BD, Muhlestein JB, Lappe DL, Whiting BM, Kolek MJ et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006; 22: 191–197.

    Article  CAS  Google Scholar 

  3. Schalekamp T, van Geest-Daalderop JHH, Kramer MHH, van Holten-Verzantvoort ATM, de Boer A . Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction. Eur J Clin Pharmacol 2007; 63: 335–343.

    Article  CAS  Google Scholar 

  4. Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL . Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91: 87–94.

    Article  CAS  Google Scholar 

  5. Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009; 5: e1000433.

    Article  Google Scholar 

  6. Mwinyi J, Nekvindova J, Cavaco I, Hofmann Y, Pedersen RS, Landman E et al. New insights into the regulation of CYP2C9 gene expression: the role of the transcription factor GATA-4. Drug Metab Dispos 2010; 38: 415–421.

    Article  CAS  Google Scholar 

  7. Chlon TM, Crispino JD . Combinatorial regulation of tissue specification by GATA and FOG factors. Development 2012; 139: 3905–3916.

    Article  CAS  Google Scholar 

  8. Arceci RJ, King AAJ, Simon MC, Orkin SH, Wilson DB . Mouse GATA-4 - a retinoic acid-inducible gata-binding transcription factor expressed in endodermally derived tissues and heart. Mol Cell Biol 1993; 13: 2235–2246.

    Article  CAS  Google Scholar 

  9. Evans T, Reitman M, Felsenfeld G . An erythrocyte-specific dna-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc Natl Acad Sci USA 1988; 85: 5976–5980.

    Article  CAS  Google Scholar 

  10. Yamamoto M, Ko LJ, Leonard MW, Beug H, Orkin SH, Engel JD . Activity and tissue-specific expression of the transcription factor nf-e1 multigene family. Genes Dev 1990; 4: 1650–1662.

    Article  CAS  Google Scholar 

  11. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu CN, Weiss MJ et al. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 1997; 90: 109–119.

    Article  CAS  Google Scholar 

  12. Weiss MJ, Orkin SH . Gata transcription factors - key regulators of hematopoiesis. Exp Hematol 1995; 23: 99–107.

    CAS  PubMed  Google Scholar 

  13. Molkentin JD . The zinc finger-containing transcription factors GATA-4,-5, and-6 - ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 2000; 275: 38949–38952.

    Article  CAS  Google Scholar 

  14. Zhu QS, Qian B, Levy D . Regulation of human microsomal epoxide hydrolase gene (EPHX1) expression by the transcription factor GATA-4. Biochim Biophys Acta 2004; 1676: 251–260.

    Article  CAS  Google Scholar 

  15. Kwintkiewicz J, Cai ZL, Stocco C . Follicle-stimulating hormone-induced activation of Gata4 contributes in the up-regulation of Cyp19 expression in rat granulosa cells. Mol Endocrinol 2007; 21: 933–947.

    Article  CAS  Google Scholar 

  16. Sumi K, Tanaka T, Uchida A, Magoori K, Urashima Y, Ohashi R et al. Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8. Mol Cell Biol 2007; 27: 4248–4260.

    Article  CAS  Google Scholar 

  17. http://www.hapmap.org.

  18. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  19. van Schie RMF, Wessels JAM, Verhoef TI, Schalekamp T, le Cessie S, van der Meer FJM et al. Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose. Pharmacogenomics 2012; 13: 1917–1923.

    Article  CAS  Google Scholar 

  20. Jacobson PA, Oetting WS, Brearley AM, Leduc R, Guan WH, Schladt D et al. Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 2011; 91: 300–308.

    Article  CAS  Google Scholar 

  21. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH . Antithrombotic and thrombolytic therapy for valvular disease antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: E576S–E600S.

    Article  CAS  Google Scholar 

  22. Sun XA, Hu SS, Qi GQ, Zhou YY . Low standard oral anticoagulation therapy for Chinese patients with St. Jude mechanical heart valves. Chin Med J 2003; 116: 1175–1178.

    PubMed  Google Scholar 

  23. Matsuyama K, Matsumoto M, Sugita T, Nishizawa J, Yoshida K, Tokuda Y et al. Anticoagulant therapy in Japanese patients with mechanical mitral valves. Circ J 2002; 66: 668–670.

    Article  CAS  Google Scholar 

  24. Yoon IK, Lee KE, Lee JK, Chang BC, Gwak HS . Adequate intensity of warfarin therapy for Korean patients with mechanical cardiac valves. J Heart Valve Dis 2013; 22: 102–109.

    PubMed  Google Scholar 

  25. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106–4112.

    Article  CAS  Google Scholar 

  26. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP 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: 2329–2333.

    Article  CAS  Google Scholar 

  27. Zhong SL, Yu XY, Liu Y, Xu D, Mai LP, Tan HH et al. Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients. Pharmacogenet Genomics 2012; 22: 176–182.

    Article  CAS  Google Scholar 

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Correspondence to H S Gwak.

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Jeong, E., Lee, K., Jeong, H. et al. Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves. Pharmacogenomics J 15, 33–37 (2015). https://doi.org/10.1038/tpj.2014.36

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