Author(s): Sefayet Karaca [*] aff1 aff2 , Nujen Colak Bozkurt aff3 , Tomris Cesuroglu aff2 aff4 , Mehmet Karaca aff5 , Mehmet Bozkurt aff6 , Erdal Eskioglu aff7 , Renato Polimanti aff8
drug response; ethnicity; pharmacogenetic algorithms; Turkey; validation study
Warfarin is the most widely used oral anticoagulant prescribed to treat and prevent thromboembolism [1 ]. Anticoagulant therapy is prescribed for different indications (e.g., deep vein thrombosis, pulmonary embolism and prevention of systemic embolism or stroke in patients with prosthetic heart valves or atrial fibrillation) [ 2 ]. Among them, atrial fibrillation is the most frequent indication since it has a prevalence of approximately 2% in the developed countries [3 ]. Warfarin therapy can reduce the risk of stroke and systemic embolism by about 60% in patients with atrial fibrillation [4 ]. Relevant risk reductions are also observed for the other warfarin indications [5 ]. Although it has a significant thromboembolism risk reduction, incorrect warfarin dosing can be associated with thromboembolic events (in the case of underdosing) or bleeding complications (in the case of overdosing) [ 6 ]. Warfarin is the first cause of emergency room visits for adverse drug events in older adults in the USA [7 ]. This is mainly due to the interindividual (i.e., differences among patients) and intraindividual (i.e., differences over time within the same patient) variability in the warfarin dose-response [2 ]. To monitor the anticoagulant effect of warfarin treatment, it is possible to measure the prothrombin time expressed as the International Normalized Ratio (INR). Specific INR ranges are used for the warfarin indications [ 8 ]. Genetic studies also contributed to improve warfarin dosing. Several polymorphisms have been associated with warfarin response. Among them, two loci play a relevant role in determining large variation in dose requirements: VKORC1 (˜30%) and CYP2C9 (˜10%) [2 ]. Numerous research groups developed different dosing algorithms based on genetic, clinical and anthropometric characteristics [9 ] on the basis of different statistical approaches [10,11 ]. Among these research groups, the International Warfarin Pharmacogenetics Consortium and few other research groups developed their algorithms in large multiethnic cohorts (comprising more than 1000 subjects) [12-15 ]. These large efforts could provide reliable indications that could help clinicians define the warfarin dose on the basis of patient characteristics. However, human genetic diversity can significantly affect the reliability of these warfarin pharmacogenetic algorithms [16,17 ], as has been demonstrated in other pharmacogenomics contexts [ 18-20 ]. In particular, some human populations with peculiar genetic features, such as the Turkish population, have not been included in these large multiethnic investigations, and no information is available about the effectiveness of these warfarin pharmacogenetic algorithms in these human groups. The genetic background of the Turkish population is an admixture of European, Middle Eastern and Central Asian ancestries [21 ]. Although Turkish people share a relevant percentage of their genetic background with Europeans, significant differences are present between Turkish and North European populations, partially explaining the health disparities of Turkish communities in Northern Europe [22,23 ]. To our knowledge, three previous studies investigated the impact of VKORC1 and CYP2C9 polymorphisms on...