Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations
- 424 Downloads
Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p < 0.001). VKORC1 GG genotype was more commonly seen in Indian patients. The mean warfarin dose in patients with GG genotype required a significant higher warfarin dose compared with those with AG and AA genotype (4.9 vs. 3.7 vs. 3.1 mg, respectively; p < 0.001). CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p < 0.01. In multivariate analysis, age, ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.
KeywordsWarfarin VKORC1 CYP2C9 Indians Gene polymorphisms
This study was funded by Research University Grant FR119/2007A.
- 2.Beyth RJ, Quinn L, Landefeld CS (2000) A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. A randomised controlled trial. Arch Intern Med 133:687–695Google Scholar
- 8.Gage BF, Eby C, Johnson JA, Deych E, Reider MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL (2004) Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 91:87–94PubMedGoogle Scholar
- 18.Lee MTM, Chen CH, Chuang HP, Lu LS, Chou CH, Wen MS et al (2009) VKORC1 haplotypes in five East Asian populations and Indians. Pharmacogenomics 10:1209–1216Google Scholar
- 34.Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG et al (2006) Different contributions of polymorphism in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African–Americans. Pharmacogenet Genomics 16:101–110PubMedCrossRefGoogle Scholar
- 35.Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N et al (2005) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5(3):e100043Google Scholar
- 38.Visser LE, Trienekens PH, De Smet PAGM et al (2005) Patients with an APOEε4 allele require lower doses of coumarin anticoagulants. Pharmacogenetics 15:69–74Google Scholar
- 42.Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Chang MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (2005) A novel functional VKORC1 Promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751PubMedCrossRefGoogle Scholar