Genetic factors in acenocoumarol treatment in Tunisian patients: Personalized medicine

The prescription of acenocoumarol (AC) in Tunisia is based on clinical algorithms with fixed doses, which are time-consuming and laborious methods that increase the risk of bleeding. Recently, two key genes in the metabolism (CYP2C9) and pharmacodynamics (VKORC1) of AC have been shown to be largely involved in the interindividual variability of therapeutic response. To determine the prevalence of genotypes and allelic frequency of VKORC1-1639G>A, VKORC1-1173C>T, CYP2C9*2 and CYP2C9*3 polymorphisms in a Tunisian cohort of patients treated with AC to evaluate their impact on the maintenance dose (MD) of AC as well as on the quality of coagulation assessed by the time in therapeutic range (TTR), and finally to propose a clinico-genetic algorithm predictive of the MD of AC. We conducted a prospective study in the department of functional explorations and cardiological resuscitation of La Rabta Hospital. We evaluated for each patient: genotyping of the VKORC1-1639G>A, VKORC1-1173C>T, CYP2C9*2 and CYP2C9*3 genes, MD of AC and TTR. We subsequently established a clinico-genetic predictive algorithm for the DM. In our study, 97 patients were included. The mean TTR was 56.4%. The frequency of GG, GA, and AA genotypes of the VKORC1-1639G>A polymorphism were 9.3%, 66%, and 24.7%, respectively. The genotype frequencies for CC, CT, and TT of the VKORC1-1173C>T polymorphism were 24.7%, 59.8%, and 15.5%, respectively. The genotype frequencies for the CYP2C9 1*/1*, 1/2*, 2*/2*, 1*/3*, 3*/3*, 2*/3* gene polymorphisms were 29.9%, 5.1%, 0%, 43.2%, 3% and 18.5%, respectively. Regarding the influence of genetic factors on MD, VKORC1-1639, VKORC1-1173C>T, CYP2C9*2 and CYP2C9*3 polymorphisms were associated with lower AC MD than wild-type genotypes (P = 0.011; P = 0.002; P = 0.032 and P = 0.021, respectively). The clinico-genetic algorithm correctly estimated AC MD for 52% of patients, whereas the clinical algorithm predicted the MD for only 30% of patients. The contribution of genetic factors to interindividual variability in CA is significant, influencing both the dose and quality of anticoagulation. The adoption of a clinical-genetic algorithm could be beneficial in determining the optimal dose for each patient.