Pharmacogenetic Aspects of Coumarinic Oral Anticoagulant Therapies

Abstract

Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gammaglutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C [ T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies.

The Role of Clinical Variables and VKORC1 Polymorphism in Efficacy and Stability of Acenocoumarol in Neurological Patients

“…[ 19 ] They noted G allele frequency in 89.6% and A allele frequency in 10.6% of patients. Two studies on Indian population have reported the GG, AG, and AA genotype frequencies of VKORC1-1639G >A polymorphism as 80%, 13%, 7% and 88.3%, 9%, 2.7%, respectively[ 20 21 ] Small study sample size may have contributed to this slight difference. In our study, female gender, rural dwelling, presence of diabetes and hypertension, use of multiple drugs such as digoxin, PPIs, and amiodarone were related to unstable INR, which is consistent with earlier reports.…”

Impact of polymorphisms of the GGCX gene on maintenance warfarin dose in Chinese populations: Systematic review and meta-analysis

“…Several studies have demonstrated that gene polymorphisms are significantly associated with warfarin dose ( Lal et al, 2006 , Pavani et al, 2012 , Rathore et al, 2011 ). Moreover, meta-analyses have revealed the genes vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 complex subunit 2C9 (CYP2C9) and cytochrome P450 complex subunit 4F2 (CYP4F2) to be significantly associated with warfarin dose ( Jorgensen et al, 2012 , Liang et al, 2011 ).…”

CYP2C9FNx013 polymorphism presenting as lethal subdural hematoma with low-dose warfarin

“…Amongst the variants, *2 and *3 are more common than the rest and exhibit lesser enzymatic activity. [ 1 ] The anticoagulant effect of warfarin is measured by prothrombin time-international normalized ratio (PT-INR). Warfarin exerts its anticoagulant effect by reducing the regeneration of active vitamin K through inhibition of vitamin K epoxide reductase, encoded by vitamin K epoxide reductase complex subunit 1 gene (VKORC1).…”