Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of ... Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR.
Association of genetic polymorphisms in the VKORC1 and CYP2C9 genes with warfarin dosage in a group of Kuwaiti individuals Maryam
1 2 3 1 1 H. Alrashid , Ahmad Al-Serri , Salem H. Alshemmari , Philip Koshi , Suzanne A. Al-Bustan
1Department of Biological Sciences, Faculty of Science, Kuwait University; 2Department of Pathology, Faculty of Medicine, Kuwait University; 3Department of
Medicine, Faculty of Medicine, Kuwait University
Introduction
Results
Warfarin is an anticoagulant that is prescribed for patients who are at risk for blood coagulation. Warfarin has a reference value for an effective dose represented by a target International Normalization Ratio of Prothrombin Times (INR) [1, 2]. The narrow therapeutic index and the large variation in the inter-individual dose for warfarin is problematic because a low dose can render the patient susceptible to thrombosis or blood clotting, while a higher dose may increase susceptibility to bleeding, which can be lethal [2]. Single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1, combined with measurable biometrics, have been shown to account for 60% of the variation in warfarin dose [3]. The association of CYP2C9 and VKORC1 polymorphisms with variation in warfarin tolerable and effective dose has been shown to differ among populations. Studies that have investigated such association and allele distribution in the Middle East are few, and little information is available on the subject for this region [4]. Different warfarin dosing algorithms have been developed that take into account the effect of the major CYP2C9 and VKORC1 SNPs effecting the dosage, however their predictive performance have been shown to vary among different populations mainly due to differences of these SNPs effect in these populations [2]. We conducted a study to investigate if an association between polymorphisms in CYP2C9 and VKORC1 SNPs and the daily maintenance warfarin dose exists in the Kuwaiti population.
For CYP2C9, carriers of CYP2C9 *1/*1 required the highest dosage (5.5±3.3 mg/day) compared to non*1/*1 carriers (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 dosage compared to variant allele carriers (p ≤ 0.001-0.002). There was no association found between the daily warfarin dose and the rs7294 polymorphism.
Methods A total of 108 Kuwaiti Patients who were taking a maintenance dose of warfarin to maintain an INR of 2.0-3.0 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 by multivariate analysis using linear regression after adjusting for sex, body mass index (BMI), and age. Kruskal-Wallis test was used for nonparametric analysis where appropriate. Data were presented as B coefficient and 95% confidence intervals (CI). Fisher’s exact test was used to compare between haplotypes. Bonferroni correction was considered for multiple testing and significance was set as p A genetic polymorphism upon warfarin dose requirement in different ethnic populations. Current Medical Research and Opinion. 2014; 8: 1505-1511. Suarez-Kurtz G. Population diversity and the performance of warfarin dosing algorithms. Br J Clin Pharmacol 2011; 72: 451–453. 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. 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.
