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Molecular Diagnosis & Therapy

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01.04.2016 | Original Research Article

Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals

verfasst von: Maryam H. Alrashid, Ahmad Al-Serri, Salem H. Alshemmari, Philip Koshi, Suzanne A. Al-Bustan

Erschienen in: Molecular Diagnosis & Therapy | Ausgabe 2/2016

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Abstract

Background and Objective

Warfarin is the most widely prescribed oral anticoagulant worldwide. The narrow therapeutic index and the large variation in the inter-individual dose of warfarin are problematic, since the side effects can be lethal. Single nucleotide polymorphisms (SNP) in CYP2C9 and VKORC1 have been shown to significantly affect warfarin dosage toleration and this effect varies among different populations. We aimed to investigate the effect of these SNPs on warfarin dosage in a sample of Kuwaiti patients.

Methods

Kuwaiti patients who were taking a maintenance dose of warfarin were genotyped for CYP2C9*1, *2 and *3 and VKORC1 rs9923231, rs9934438, rs7294 and rs2884737. The association of these SNPs with the warfarin dose was evaluated.

Results

For CYP2C9, the CYP2C9 *1/*1 genotype required a higher dose (5.5 ± 3.3 mg/day) compared to non-*1/*1 (3.3 ± 1.7 mg/day) (p = 0.003). For VKORC1, the daily warfarin dose was significantly different (p = 0.001) among the three genotypes of rs9923231, rs9934438 and rs2884737, with carriers of the wild-type genotype requiring the highest dose compared to variant allele carriers (p ≤ 0.001–0.002). There was no association found between the daily warfarin dose and the rs7294 polymorphism.

Conclusions

Our data showed that individuals carrying the wild-type allele of CYP2C9 or VKORC1 rs9923231, rs9934438 or rs2884737 are less sensitive than individuals with the variant alleles of these SNPs and therefore required a higher daily maintenance dose of warfarin. Our study confirms the association between SNPs in CYP2C9 and VKORC1 and warfarin dose tolerance in Kuwaiti patients.

Jin B, Hong Y, Zhu J, Li Y, Shi H-M. The impact of VKORC1-1639G>A genetic polymorphism upon warfarin dose requirement in different ethnic populations. Curr Med Res Opin. 2014;8:1505–11.CrossRef

Ramos E, Doumatey A, Elkahloun AG, Shriner D, Huang H, Chen G, et al. Pharmacogenomics, ancestry and clinical decision making for global populations. Pharmacogenomics J. 2014;3:217–22.CrossRef

Suarez-Kurtz G. Population diversity and the performance of warfarin dosing algorithms. Br J Clin Pharmacol. 2011;72:451–3.CrossRefPubMedPubMedCentral

Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427(6974):541–4.CrossRefPubMed

Van Booven D, Marsh S, McLeod H, Carrillo MW, Sangkuhl K, Klein TE, et al. Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genomics. 2010;20(4):277–81.PubMedPubMedCentral

Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427(6974):537–41.CrossRefPubMed

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(7):2329–33.CrossRefPubMed

Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005;5(4):262–70.CrossRefPubMed

Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63(2):437–59.CrossRefPubMed

10.

Fung E, Patsopoulos NA, Belknap SM, O’Rourke DJ, Robb JF, Anderson JL, et al. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost. 2012;8:893–904.

11.

Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res. 2014;134(3):537–44.CrossRefPubMed

12.

Suarez-Kurtz G, Botton MR. Pharmacogenomics of warfarin in populations of African descent. Br J Clin Pharmacol. 2013;75(2):334–46.CrossRefPubMedPubMedCentral

13.

Owen RP, Gong L, Sagreiya H, Klein TE, Altman RB. VKORC1 pharmacogenomics summary. Pharmacogenet Genomics. 2010;20(10):642–4.CrossRefPubMedPubMedCentral

14.

Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS One. 2012;7(8):e44064. doi:10.1371/journal.pone.0044064.CrossRefPubMedPubMedCentral

15.

Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood. 2005;106(1):135–40.CrossRefPubMed

16.

Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J. 2003;3(4):202–14.CrossRefPubMed

17.

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(18):3827–34.CrossRefPubMedPubMedCentral

18.

Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther. 2008;83(2):312–21.CrossRefPubMedPubMedCentral

19.

Perera MA, Cavallari LH, Limdi NA, Gamazon ER, Konkashbaev A, Daneshjou R, et al. Genetic variants associated with warfarin dose in African–American individuals: a genome-wide association study. Lancet. 2013;382(9894):790–6.CrossRefPubMedPubMedCentral

20.

Cooper GM, Johnson JA, Langaee TY. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood. 2008;112:1022–7.CrossRefPubMedPubMedCentral

21.

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

22.

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(13):1745–51.CrossRefPubMed

23.

Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625–9.CrossRefPubMedPubMedCentral

24.

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:Article ID 315980.

25.

Saab YB, Langaee T. Genetic polymorphisms of CYP2C9: comparison of prevalence in the lebanese population with other populations. Pharmacol Pharm. 2011;2(2):88–93.CrossRef

26.

El Din MS, Amin DG, Ragab SB, et al. Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen. Int J Lab Hematol. 2012;34:517–24.CrossRefPubMed

27.

Samar H, Masahiro H, Kaori N, Mervat E, Nadia M, Mohammed A, Michiano M. Allele and genotype frequencies of polymorphic cytochromes P 450 (CYP2C9, CYP2C19, CYP2EI) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol. 2002;53(6):596–603.CrossRef

28.

Dorado P, Sosa-Macias MG, Peñas-LLedó EM, Alanis-Bañuelos RE, Wong M-L, Licinio J, et al. CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards. Pharmacogenomics J. 2011;11:108–12.CrossRefPubMed

29.

Tanira MO, Al-Mukhaini MK, Al-Hinai AT, Al Balushi KA, Ahmed IS. Frequency of CYP2C9 genotypes among omani patients receiving warfarin and its correlation with warfarin dose. Community Genet. 2007;10(1):32–7.CrossRefPubMed

30.

Hamdy SI, Hiratsuka M, Narahara K, El-Enany M, Moursi N, Ahmed MS, et al. Allele and Genotype Frequencies of Polymorphic Cytochromes P 450 (CYP2C9, CYP2C19, CYP2EI) and Dihydropyrimidine Dehydrogenase (DPYD) in the Egyptian Population. Br J Clin Pharmacol. 2002;53(6):596–603.CrossRefPubMedPubMedCentral

Titel: Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals
verfasst von: Maryam H. Alrashid
Ahmad Al-Serri
Salem H. Alshemmari
Philip Koshi
Suzanne A. Al-Bustan
Publikationsdatum: 01.04.2016
Verlag: Springer International Publishing
Erschienen in: Molecular Diagnosis & Therapy / Ausgabe 2/2016
Print ISSN: 1177-1062
Elektronische ISSN: 1179-2000
DOI: https://doi.org/10.1007/s40291-016-0190-7

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Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals