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The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population

Abstract

The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. The population was stratified into derivation and validation cohorts for the dosing model. The minor allele frequency (MAF) of VKORC1 (−1639G>A) was A (0.47), while the MAF’s for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one CYP2C9 decreased function allele (*2 or *3) required lower median (IQR) warfarin doses compared to noncarriers [24.5 (14.5) mg/week vs. 35 (21) mg/week, p < 0.001]. Similarly, carriers of each additional copy of (A) variant in VKORC1 (−1639G>A) led to reduction in warfarin dose requirement compared to noncarriers [21(7.5) vs. 31.5(18.7) vs. 43.7(15), p < 0.0001]. CYP4F2*3 polymorphism on the other hand was not associated with warfarin dose. Multivariate analysis on the derivation cohort (n = 104) showed that a dosing model consisting of hypertension (HTN), heart failure (HF), VKORC1 (−1639G>A), CYP2C9*2 & *3, and smoking could explain 39.2% of warfarin dose variability in Qataris (P < 0.001). In the validation cohort (n = 45), correlation between predicted and actual warfarin doses was moderate (Spearman’s rho correlation coefficient = 0.711, p < 0.001). This study concluded that VKORC1 (−1639G>A), CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with HTN, HF and smoking.

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References

  1. 1.

    Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e44S–e88S.

    CAS  Article  Google Scholar 

  2. 2.

    Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis. 2006;21:73–7.

    Article  Google Scholar 

  3. 3.

    Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128:1300–5. e2.

    Article  Google Scholar 

  4. 4.

    Gong X, Gutala R, Jaiswal AK. Quinone oxidoreductases and vitamin K metabolism. Vitam Horm. 2008;78:85–101.

    CAS  Article  Google Scholar 

  5. 5.

    Oldenburg J, Marinova M, Muller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm. 2008;78:35–62.

    CAS  Article  Google Scholar 

  6. 6.

    Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol. 2003;41:1633–52.

    CAS  Article  Google Scholar 

  7. 7.

    Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. J Am Coll Cardiol. 1993;95:315–28.

    CAS  Google Scholar 

  8. 8.

    Nunnelee JD. Review of an Article: The International Warfarin Pharmacogenetics Consortium (2009). Estimation of the warfarin dose with clinical and pharmacogenetic data. NEJM 360 (8): 753-64. J Vasc Nurs. 2009;27:109.

    Article  Google Scholar 

  9. 9.

    Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, 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.

    CAS  Article  Google Scholar 

  10. 10.

    Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369:2294–303.

    CAS  Article  Google Scholar 

  11. 11.

    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 

  12. 12.

    Elewa HAA, Al-Rawi S, Nounou A, Mahmoud H, Singh R. Trends in oral anticoagulant use in Qatar: a five-year experience. J Thromb Thrombolysis. 2016;43:411–6.

    Article  Google Scholar 

  13. 13.

    Bader LA, Elewa H. The impact of genetic and non-genetic factors on warfarin dose prediction in MENA region: a systematic review. PLoS ONE. 2016;11:e0168732.

    Article  Google Scholar 

  14. 14.

    Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics. 2011;21:130–5.

    CAS  Article  Google Scholar 

  15. 15.

    Invitrogen. PureLink® Genomic DNA Kits For purification of genomic DNA.2017. https://tools.thermofisher.com/content/sfs/manuals/purelink_genomic_man.pdf.

  16. 16.

    PrepITL2P. Laboratory protocol for manual purification of DNA from 0.5 mL of sample. DNA genotek. 2015;01.

  17. 17.

    Omberg L, Salit J, Hackett N, Fuller J, Matthew R, Chouchane L, et al. Inferring genome-wide patterns of admixture in Qataris using fifty-five ancestral populations. BMC Genet. 2012;13:49.

    Article  Google Scholar 

  18. 18.

    Sandridge AL, Takeddin J, Al-Kaabi E, Frances Y. Consanguinity in Qatar: knowledge, attitude and practice in a population born between 1946 and 1991. J Biosoc Sci. 2010;42:59–82.

    CAS  Article  Google Scholar 

  19. 19.

    Hunter-Zinck H, Musharoff S, Salit J, Al-Ali KA, Chouchane L, Gohar A, et al. Population genetic structure of the people of Qatar. Am J Hum Genet. 2010;87:17–25.

    CAS  Article  Google Scholar 

  20. 20.

    Sivadas A, Sharma P, Scaria V. Landscape of warfarin and clopidogrel pharmacogenetic variants in Qatari population from whole exome datasets. Pharmacogenomics. 2016;17:1891–901.

  21. 21.

    Alrashid MH, Al-Serri A, Alshemmari SH, Koshi P, Al-Bustan SA. Association of genetic polymorphisms in the VKORC1 and CYP2C9 genes with warfarin dosage in a group of Kuwaiti individuals. Mol Diagn Ther. 2016;20:183–90.

    CAS  Article  Google Scholar 

  22. 22.

    Özer M, Demirci Y, Hizel C, Sarikaya S, Karalti İ, Kaspar Ç, et al. Impact of genetic factors (CYP2C9, VKORC1 and CYP4F2) on warfarin dose requirement in the Turkish population. Basic Clin Pharm Toxicol. 2013;112:209–14.

    Article  Google Scholar 

  23. 23.

    Alzahrani AM, Ragia G, Hanieh H, Manolopoulos VG. Genotyping of CYP2C9 and VKORC1 in the Arabic population of Al-Ahsa, Saudi Arabia. Biomed Res Int. 2013;2013:315980. https://doi.org/10.1155/2013/315980.

  24. 24.

    Loebstein R, Vecsler M, Kurnik D, Austerweil N, Gak E, Halkin H, et al. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Clin Pharmacol Ther. 2005;77:365–72.

    CAS  Article  Google Scholar 

  25. 25.

    Ghozlan MF, Foad DA, Darwish YW, Saad AA. Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome. Blood Coagul Fibrinolysis. 2015;26:499–504.

    CAS  Article  Google Scholar 

  26. 26.

    Al-Eitan LN, Almasri AY, Khasawneh RH. Impact of CYP2C9 and VKORC1 polymorphisms on warfarin sensitivity and responsiveness in Jordanian cardiovascular patients during the initiation therapy. Genes. 2018;9:578.

    Article  Google Scholar 

  27. 27.

    Shrif NE, Won HH, Lee ST, Park JH, Kim KK, Kim MJ, et al. Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients. Eur J Clin Pharmacol. 2011;67:1119–30.

    CAS  Article  Google Scholar 

  28. 28.

    Namazi S, Azarpira N, Hendijani F, Khorshid MB, Vessal G, Mehdipour AR. The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran. Clin Ther. 2010;32:1050–60.

    CAS  Article  Google Scholar 

  29. 29.

    Xie HG, Prasad HC, Kim RB, Stein CM. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev. 2002;54:1257–70.

    CAS  Article  Google Scholar 

  30. 30.

    Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood. 2010;115:3827–34.

    CAS  Article  Google Scholar 

  31. 31.

    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. Hum Genet. 2007;121:23–34.

    CAS  Article  Google Scholar 

  32. 32.

    Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41.

    CAS  Article  Google Scholar 

  33. 33.

    Shahin MH, Cavallari LH, Perera MA, Khalifa SI, Misher A, Langaee T, et al. VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians. Thrombosis Haemost. 2013;109:1045–50.

    CAS  Article  Google Scholar 

  34. 34.

    Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharm. 2008;64:889–94.

    CAS  Article  Google Scholar 

  35. 35.

    Vecsler M, Loebstein R, Almog S, Kurnik D, Goldman B, Halkin H, et al. Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin. J Thromb Haemost. 2006;95:205–11.

    CAS  Article  Google Scholar 

  36. 36.

    Yousef AM, Bulatova NR, Newman W, Hakooz N, Ismail S, Qusa H, et al. Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population. Mol Biol Rep. 2012;39:9423–33.

    CAS  Article  Google Scholar 

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Correspondence to Hazem Elewa.

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Bader, L., Mahfouz, A., Kasem, M. et al. The effect of genetic and nongenetic factors on warfarin dose variability in Qatari population. Pharmacogenomics J 20, 277–284 (2020). https://doi.org/10.1038/s41397-019-0116-y

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