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CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis

The Pharmacogenomics Journal volume 20, pages 306–319 (2020)Cite this article

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Abstract

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = −0.610, 95% CI: −0.802 to −0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = −0.666, 95% CI: −0.887 to −0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: −0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

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References

  1. Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Walraven C. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ. 2008;179:235–44.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci. 2009;30:375–86.

    Article  CAS  PubMed  Google Scholar 

  3. Kamali F, Wynne H. Pharmacogenetics of warfarin. Annu Rev Med. 2010;61:63–75.

    Article  CAS  PubMed  Google Scholar 

  4. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. New Engl J Med. 2011;364:1144–53.

    Article  CAS  PubMed  Google Scholar 

  5. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. New Engl J Med. 2005;352:2285–93.

    Article  CAS  PubMed  Google Scholar 

  6. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. New Engl J Med. 2009;360:753–64.

    Article  CAS  PubMed  Google Scholar 

  7. Li C, Schwarz UI, Ritchie MD, Roden DM, Stein CM, Kurnik D. Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood. 2009;113:3925–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis. Thrombosis Res. 2010;125:e159–66.

    Article  CAS  Google Scholar 

  9. Liang R, Wang C, Zhao H, Huang J, Hu D, Sun Y. Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thrombosis Res. 2012;130:38–44.

    Article  CAS  Google Scholar 

  10. Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102:397–404.

    Article  CAS  PubMed  Google Scholar 

  11. Biss TT, Avery PJ, Brandao LR, Chalmers EA, Williams MD, Grainger JD, et al. VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Blood. 2012;119:868–73.

    Article  CAS  PubMed  Google Scholar 

  12. Hirai K, Hayashi H, Ono Y, Izumiya K, Tanaka M, Suzuki T, et al. Influence of CYP4F2 polymorphisms and plasma vitamin K levels on warfarin sensitivity in Japanese pediatric patients. Drug Metab Pharmacokinet. 2013;28:132–7.

    Article  CAS  PubMed  Google Scholar 

  13. Kamal El-Din MA, Farhan MS, El Shiha RI, El-Kaffas RM, Mousa SM. Frequency of CYP2C9 and VKORC1 gene polymorphisms and their influence on warfarin dose in Egyptian pediatric patients. Paediatr Drugs. 2014;16:337–41.

    Article  PubMed  Google Scholar 

  14. Kato Y, Ichida F, Saito K, Watanabe K, Hirono K, Miyawaki T, et al. Effect of the VKORC1 genotype on warfarin dose requirements in Japanese pediatric patients. Drug Metab Pharmacokinet. 2011;26:295–9.

    Article  CAS  PubMed  Google Scholar 

  15. Moreau C, Bajolle F, Siguret V, Lasne D, Golmard JL, Elie C, et al. Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood. 2012;119:861–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nguyen N, Anley P, Yu MY, Zhang G, Thompson AA, Jennings LJ. Genetic and clinical determinants influencing warfarin dosing in children with heart disease. Pediatr Cardiol. 2013;34:984–90.

    Article  PubMed  Google Scholar 

  17. Nowak-Gottl U, Dietrich K, Schaffranek D, Eldin NS, Yasui Y, Geisen C, et al. In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood. 2010;116:6101–5.

    Article  CAS  PubMed  Google Scholar 

  18. Shaw K, Amstutz U, Hildebrand C, Rassekh SR, Hosking M, Neville K, et al. VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatr Blood cancer. 2014;61:1055–62.

    Article  CAS  PubMed  Google Scholar 

  19. Vear SI, Ayers GD, Van Driest SL, Sidonio RF, Stein CM, Ho RH. The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. Br J Haematol. 2014;165:832–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang J, Tian L, Zhang Y, Shen J. The influence of VKORC1 gene polymorphism on warfarin maintenance dosage in pediatric patients: a systematic review and meta-analysis. Thrombosis Res. 2015;136:955–61.

    Article  CAS  Google Scholar 

  21. Zhang J, Tian L, Huang J, Huang S, Chai T, Shen J. Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: a systematic review and meta-analysis. Cardiovasc Ther. 2017;35:26–32.

    Article  CAS  PubMed  Google Scholar 

  22. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2008. http://handbook.cochrane.org/index.htm#part_3_special_topics.html. Accessed 14 Jan 2018.

  23. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.

    Article  PubMed  Google Scholar 

  24. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.

    Article  PubMed  Google Scholar 

  25. Takeuchi M, Kobayashi T, Brandao LR, Ito S. Effect of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin maintenance dose in children aged less than 18 years: a protocol for systematic review and meta-analysis. Syst Rev. 2016;5:105.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wells G, Shea B, O’Connell DL, Peterson J, Welch V, Losos M, et al. The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. Appl Engi Agri. 2014;18:727–34.

  27. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement. Eur J Epidemiol. 2009;24:37–55.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Flockhart DA, O’Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008;10:139–50.

    Article  CAS  PubMed  Google Scholar 

  29. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  30. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  31. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence-publication bias. J Clin Epidemiol. 2011;64:1277–82.

    Article  PubMed  Google Scholar 

  32. Biss T, Hamberg AK, Avery P, Wadelius M, Kamali F. Warfarin dose prediction in children using pharmacogenetics information. Br J Haematol. 2012;159:106–9.

    Article  CAS  PubMed  Google Scholar 

  33. Hamberg AK, Friberg LE, Hanseus K, Ekman-Joelsson BM, Sunnegardh J, Jonzon A, et al. Warfarin dose prediction in children using pharmacometric bridging-comparison with published pharmacogenetic dosing algorithms. Eur J Clin Pharmacol. 2013;69:1275–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lojo L, Duconge J, Santiago-Borrero P. Integrating combinatorial CYP2C9 and VKORC1 genotypes into clinical warfarin management in Puerto Rican children with thrombosis: an illustrative case study. Abstract presented at 23rd Annual Meeting of the American Society of Pediatric Hematology/Oncology (ASPHO), Montreal, Quebec; 2010.

  35. Mitchell LG, Nowak-Gottl U, Schaffranek D, et al. The CYP4F2 V433M Polymorphism does not correlate with vitamin k antagonist dosing in a pediatric population. In: 23rd Congress of the International Society on Thrombosis and Haemostasis 57th Annual SSC Meeting. Kyoto, Japan; 2011. p. 437.

  36. Bomgaars L, Massicotte MP, Thornburg C, et al. Pharmacogenetic expert dosing strategies (PEDS) for warfarin. J Thrombosis Haemost. 2011;9:287–287.

    Google Scholar 

  37. Hamberg AK, Wadelius M, Friberg LE, Biss TT, Kamali F, Jonsson EN. Characterizing variability in warfarin dose requirements in children using modelling and simulation. Br J Clin Pharmacol. 2014;78:158–69.

    Article  CAS  PubMed  Google Scholar 

  38. Beaune P. Pharmacogenetics and other factors in individualization of oral anti-vitamine k anti-coagulants. Clin Ther. 2013;35:e113.

  39. Lala M, Burckart GJ, Takao CM, Pravica V, Momper JD, Gobburu JV. Genetics-based pediatric warfarin dosage regimen derived using pharmacometric bridging. J Pediatr Pharmacol therapeutics. 2013;18:209–19.

    Article  Google Scholar 

  40. Hawcutt DB, Ghani AA, Sutton L, Jorgensen A, Zhang E, Murray M, et al. Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects. Pharmacogenomics J. 2014;14:542–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tabib A, Najibi B, Dalili M, Baghaei R, Poopak B. Enzyme polymorphism in warfarin dose management after pediatric cardiac surgery. Res Cardiovasc Med. 2015;4:e27963.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dilge Taskin B, Kula S, Ergun MA, Altun D, Olgunturk R, Tunaoglu FS, et al. The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population. Anatol J Cardiol. 2016;16:791–6.

    PubMed  Google Scholar 

  43. Marek E, Momper JD, Hines RN, Takao CM, Gill JC, Pravica V, et al. Prediction of warfarin dose in pediatric patients: an evaluation of the predictive performance of several models. J Pediatr Pharmacol Ther. 2016;21:224–32.

    PubMed  PubMed Central  Google Scholar 

  44. Wakamiya T, Hokosaki T, Tsujimoto S, Kadota K, Nakano Y, Watanabe S, et al. Effect of VKORC1, CYP2C9, CFP4F2, and GGCX gene polymorphisms on warfarin dose in Japanese pediatric patients. Mol diagnosis Ther. 2016;20:393–400.

    Article  CAS  Google Scholar 

  45. Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Gottl U, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e737S–e801S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Danese E, Montagnana M, Johnson JA, Rettie AE, Zambon CF, Lubitz SA, et al. Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis. Clin Pharmacol Ther. 2012;92:746–56.

    Article  CAS  PubMed  Google Scholar 

  47. Cioffi M, Molinari AM, Gazzerro P, Di Finizio B, Fratta M, Deufemia A, et al. Serum osteocalcin in 1634 healthy children. Clin Chem. 1997;43:543–5.

    Article  CAS  PubMed  Google Scholar 

  48. Theuwissen E, Magdeleyns EJ, Braam LA, Teunissen KJ, Knapen MH, Binnekamp IA, et al. Vitamin K status in healthy volunteers. Food Funct. 2014;5:229–34.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge Alanna Marson, a reference and instruction librarian of the hospital library and archives at the hospital for sick children, for help with the literature search. We also thank Conn Hastings, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this paper.

Author information

Author notes

  1. These author contributed equally: Masanobu Takeuchi, Tohru Kobayashi

  2. These author contributed equally: Leonardo R. Brandão, Shinya Ito

Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada

    Masanobu Takeuchi, Tohru Kobayashi & Shinya Ito

  2. Department of Pediatrics, Yokohama City University, School of Medicine, Yokohama, Kanagawa, Japan

    Masanobu Takeuchi, Takuya Wakamiya & Masakatsu Yanagimachi

  3. Division of Clinical Research Planning, Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan

    Tohru Kobayashi

  4. Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, UK

    Tina Biss & Farhad Kamali

  5. Department of Haematology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    Tina Biss & Farhad Kamali

  6. Division of Pediatric Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, OH, US

    Susan I. Vear

  7. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, US

    Richard H. Ho

  8. Assistance Publique Hôpitaux de Paris, Hôpital Necker Enfants Malades, Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence M3C, Paris, France

    Fanny Bajolle

  9. University Paris Descartes, Paris, France

    Fanny Bajolle

  10. Université Paris Descartes, Inserm Unité Mixte de Recherche (UMR)-S, Paris, France

    Marie-Anne Loriot

  11. University Paris Descartes, INSERM UMR 1147, Paris, France

    Marie-Anne Loriot

  12. Influenza and Emerging Respiratory Pathogens, BC Centre for Disease Control, Vancouver, BC, Canada

    Kaitlyn Shaw

  13. Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    Bruce C. Carleton

  14. Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Anna-Karin Hamberg & Mia Wadelius

  15. Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Keiichi Hirono

  16. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Masato Taguchi

  17. Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Takuya Wakamiya

  18. Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan

    Masakatsu Yanagimachi

  19. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

    Keita Hirai & Kunihiko Itoh

  20. Division of Pediatric Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada

    Leonardo R. Brandão

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  1. Masanobu Takeuchi
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Contributions

SI and LRB initiated the study planning and all contributed to the study design. MT collected data, performed statistical analysis, interpreted the results, and drafted the paper. TK designed the study and collected data. TB, FK, SV, RH, KS, BC, AH, MW, HK, MT, TW, MY, KH, and KI provided data for the study. TK, LRB, and SI critically revised the paper. All authors read, provided feedback, and approved the final paper.

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Correspondence to Shinya Ito.

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Conflict of interest

SI received grants from Novartis Pharma AG, grants from UCB Pharma Gmbh, personal fees from AbbVie, outside the submitted work; and he is a member of the American Society of Clinical Pharmacology & Therapeutics, and the Canadian Society of Pharmacology and Therapeutics. He is also one of the Associate Editors of “Clinical Pharmacology & Therapeutics”, which conducts peer-review and publishes articles, some of which include CPIC guidelines and original articles on pharmacogenomics/genetics. The remaining authors declare that they have no conflict of interest.

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Takeuchi, M., Kobayashi, T., Biss, T. et al. CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis. Pharmacogenomics J 20, 306–319 (2020). https://doi.org/10.1038/s41397-019-0117-x

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