Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

Abstract

The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G4A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R 2 ¼ 0.45).

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review

“…These include variants in the following genes: CYP4F2 , EPHX1 , GGCX1 , MDR1 , factor VII , APOE , CALU and PZ . The MAF for the CYP4F2 (rs2108622) was 40% among Turkish [42], 30% in Omani [40] and 42% in Egyptians [12]. The EPHX1 encodes for a putative subunit of the vitamin K epoxide reductase complex called: microsomal epoxide hydrolase 1 [10].…”

“…This variant alone was able to explain 45% of the dose variability in Omani [40]. The VKORC1 Asp36Tyr was significantly associated with higher warfarin doses in Egyptians and when added to Shahin et al dosing model it further explained the variability by only 2% [30].…”

“…Only 3 studies in three different populations of MENA -Egyptian, Omani, and Turkish- have investigated the association between warfarin dose and that gene variant. These studies have shown no significant association between CYP4F2 gene variant and warfarin dose in Egyptians neither in Omani, despite its high frequency [12, 40]. A significant association between CYP4F2 gene variant and warfarin dose was among Turkish by Özer et.…”

Estimation and Validation of Acenocoumarol Dosing Algorithms In Bulgarian Patients with Cardiovascular Diseases

“…Other studies also demonstrated the influence of age on the dosage of acenocoumarol, but the mechanism of this association has not been fully elucidated yet. [8,[30][31][32][33].…”

Acenocoumarol Pharmacogenetic Dosing Algorithms and Their Application in Two Bulgarian Patients with Low Anticoagulant Requirements

“…There are many pharmacogenetic algorithms, previously developed for warfarin in different population groups Huang et al 2009;Mazzaccara et al 2013;Miao et al 2007;Pathare et al 2012;Tham et al 2006;Wei et al 2012), but these for acenocoumarol are considerably less and insufficient (Borobia et al 2012;Cerezo-Manchado et al 2013;Krishna Kumar et al 2013;Markatos et al Table 4 The results from genotyping of selected polymorphic variants in both Bulgarian patients . We used univariate and multivariate linear regression analyses to evaluate major genetic and non-genetic factors and their influence on maintenance of daily dose acenocoumarol in studied cohort of patients.…”