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The rs2108622 polymorphism is related to the early risk of ischemic stroke in non-valvular atrial fibrillation subjects under oral anticoagulation

The Pharmacogenomics Journal volume 18, pages 652–656 (2018)Cite this article

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Abstract

Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS. Clinical variables, CHADS2-VASC score and data about the international normalized ratio (INR) within the therapeutic range were all recorded. DNA was extracted from blood and genotyping was carried out by DNA sequencing. The main endpoint was the time from VKA onset to IS. Of a total of 356 consecutive IS patients monitored, 33 were included in the study. The median time to the event was 2248.0 days (interquartile range [IQR] 896.3–3545.3). The median CHADS2-VASC score was 4.0 (IQR 3.0–6.0). When we considered the risk of IS within 2 years under VKA treatment, we found that only the rs2108622 AA genotype was significantly associated with this endpoint (early IS) (hazard ratio 6.81, 95% CI 1.37–33.92, p = 0.019). Kaplan-Meier curve analysis also showed a significant relationship between early IS and rs2108622 AA genotype (Log rank p = 0.022). The CYP4F2 gene rs2108622 polymorphism was associated with a risk of early IS in NV-AF patients under VKA treatment.

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References

  1. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: european perspective. Clin Epidemiol. 2014;6:213–20.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 2001;285:2370–75.

    Article  CAS  PubMed  Google Scholar 

  3. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts: the task force for the management of atrial fibrillation of the european society of cardiology (esc)developed with the special contribution of the european heart rhythm association (ehra) of the escendorsed by the european stroke organisation (eso). Eur Heart J. 2016;37:2893–962

  4. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: Analysis of randomized clinical trials. Stroke 2002;33:2722–27.

    Article  CAS  PubMed  Google Scholar 

  5. European Heart Rhythm A, European Association for Cardio-Thoracic S, Camm AJ, Kirchhof P, Lip GY, Schotten U, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the european society of cardiology (esc). Eur Heart J 2010;31:2369–429.

  6. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67.

    Article  PubMed  Google Scholar 

  7. McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. Cyp4f2 is a vitamin k1 oxidase: an explanation for altered warfarin dose in carriers of the v433m variant. Mol Pharmacol 2009;75:1337–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, et al. Association of warfarin dose with genes involved in its action and metabolism. Human Genet 2007;121:23–34.

    Article  CAS  Google Scholar 

  9. Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, et al. A genome-wide association study confirmsvkorc1, cyp2c9, and cyp4f2 as principal genetic determinants of warfarin dose. PLoS Genet 2009;5:e1000433.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common vkorc1 and ggcx polymorphisms associated with warfarin dose. Pharm J 2005;5:262–70.

    CAS  Google Scholar 

  11. Wu AH. Use of genetic and nongenetic factors in warfarin dosing algorithms. Pharmacogenomics 2007;8:851–61.

    Article  CAS  PubMed  Google Scholar 

  12. Fernandez-Cadenas I, Del Rio-Espinola A, Giralt D, Domingues-Montanari S, Quiroga A, Mendioroz M, et al. Il1b and vwf variants are associated with fibrinolytic early recanalization in patients with ischemic stroke. Stroke 2012;43:2659–65.

    Article  CAS  PubMed  Google Scholar 

  13. Sorensen IF, Vazquez AI, Irvin MR, Sorensen P, Davis BR, Ford CE, et al. Pharmacogenetic effects of ‘candidate gene complexes’ on stroke in the genhat study. Pharm Genom 2014;24:556–63.

    Article  CAS  Google Scholar 

  14. Magvanjav O, McDonough CW, Gong Y, McClure LA, Talbert RL, Horenstein RB, et al. Pharmacogenetic associations of beta1-adrenergic receptor polymorphisms with cardiovascular outcomes in the sps3 trial (secondary prevention of small subcortical strokes). Stroke 2017;48:1337–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yi X, Zhou Q, Wang C, Lin J, Liu P, Fu C. Platelet receptor gene (p2y12, p2y1) and platelet glycoprotein gene (gpiiia) polymorphisms are associated with antiplatelet drug responsiveness and clinical outcomes after acute minor ischemic stroke. Eur J Clin Pharmacol 2017;73:437–43.

    Article  CAS  PubMed  Google Scholar 

  16. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the american heart association/american stroke association stroke council; council on cardiovascular surgery and anesthesia; council on cardiovascular radiology and intervention; council on cardiovascular nursing; and the interdisciplinary council on peripheral vascular disease. The American academy of neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009;40:2276–93.

    Article  PubMed  Google Scholar 

  17. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72.

    Article  PubMed  Google Scholar 

  18. Meng C, Wang J, Ge WN, Tang SC, Xu GM. Correlation between cyp4f2 gene rs2108622 polymorphism and susceptibility to ischemic stroke. Int J Clin Exp Med 2015;8:16122–26.

    PubMed  PubMed Central  Google Scholar 

  19. 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. Thromb Res 2012;130:38–44.

    Article  CAS  PubMed  Google Scholar 

  20. Wu CC, Gupta T, Garcia V, Ding Y, Schwartzman ML. 20-Hete and blood pressure regulation: clinical implications. Cardiol Rev 2014;22:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from theamerican heart association/american stroke association. Stroke 2014;45:3754–32.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Munshi A, Sharma V, Kaul S, Al-Hazzani A, Alshatwi AA, Shafi G, et al. Association of 1347 g/a cytochrome p450 4f2 (cyp4f2) gene variant with hypertension and stroke. Mol Biol Rep 2012;39:1677–82.

    Article  CAS  PubMed  Google Scholar 

  23. Pengo V, Zambon CF, Fogar P, Padoan A, Nante G, Pelloso M, et al. A randomized trial of pharmacogenetic warfarin dosing in naive patients with non-valvular atrial fibrillation. PLoS One 2015;10:e0145318.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shaw K, Amstutz U, Kim RB, Lesko LJ, Turgeon J, Michaud V, et al. Clinical practice recommendations on genetic testing of cyp2c9 and vkorc1 variants in warfarin therapy. Ther Drug Monit 2015;37:428–36.

    Article  CAS  PubMed  Google Scholar 

  25. Zambon CF, Pengo V, Padrini R, Basso D, Schiavon S, Fogar P, et al. Vkorc1, cyp2c9 and cyp4f2 genetic-based algorithm for warfarin dosing: an italian retrospective study. Pharmacogenomics 2011;12:15–25.

    Article  CAS  PubMed  Google Scholar 

  26. Kuznetsov S, Barcelona R, Josephson RA, Mohan SK. The role of nonvitamin k antagonist oral anticoagulants (noacs) in stroke prevention in patients with atrial fibrillation. Curr Neurol Neurosci Rep 2016;16:47.

    Article  PubMed  Google Scholar 

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Acknowledgements

We are indebted to the plasma donors for their support and permission. Samples were obtained with the support of IRBLleida biobank and RETICS BIOBANCOS (RD09/0076/00059).

Author contributions

LCC—Design and conceptualization of the study. Analysis and interpretation of the data. Drafting and revision of the manuscript for intellectual content. JLR—Design and conceptualization of the study. Analysis and interpretation of the data. Drafting and revision of the manuscript for intellectual content. MVM—Analysis and interpretation of the data. Revision of the manuscript for intellectual content. CM—Analysis and interpretation of the data. Revision of the manuscript for intellectual content. JMS—Analysis and interpretation of the data. Revision of the manuscript for intellectual content. IB—Analysis and interpretation of the data. Revision of the manuscript for intellectual content. SC—Design and conceptualization of the study. Analysis and interpretation of the data. Drafting and revision of the manuscript for intellectual content. FP—Design and conceptualization of the study. Analysis and interpretation of the data. Drafting and revision of the manuscript for intellectual content.

Funding

Funding

This work has been supported by the Agència de Gestió d’Ajuts Universitaris i de Recerca of the Autonomous Government of Catalonia [2014SGR-1418] and by the TV3 Marató Foundation [95/C/2011].

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Authors and Affiliations

  1. Clinical Neurosciences Group, Institut de Recerca Biomèdica de Lleida (IRBLleida). Universitat de Lleida (UdL), Lleida, Spain

    L. Colàs-Campàs, M. V. Montserrat, J. Molina-Seguín, I. Benabdelhak, S. Cambray & F. Purroy

  2. Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, Universidad de Málaga, Malaga, Spain

    J. L. Royo

  3. Hemostasis Department, Hospital Arnau de Vilanova, Lleida, Spain

    C. Marzo

  4. Stroke Unit, Clinical Neurosciences Group, Hospital Universitari Arnau de Vilanova, Lleida, Spain

    J. Molina-Seguín, I. Benabdelhak & F. Purroy

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  1. L. Colàs-Campàs
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Correspondence to F. Purroy.

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F. Purroy and S. Cambray contributed equally to this work.

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Colàs-Campàs, L., Royo, J.L., Montserrat, M.V. et al. The rs2108622 polymorphism is related to the early risk of ischemic stroke in non-valvular atrial fibrillation subjects under oral anticoagulation. Pharmacogenomics J 18, 652–656 (2018). https://doi.org/10.1038/s41397-017-0007-z

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