CYP2C9, VKORC1, CYP4F2, ABCB1 and F5 variants: Inﬂuence on quality of long-term anticoagulation Risha Nahar a,b,c, *, Renu Saxena b,f , Roumi Deb c,f , Rajiv Parakh d,f , Sujay Shad e,f , Prahlad K. Sethi f , Parul Takkar g,f , Ishwar C. Verma b a Krishna Institute of Medical Sciences (KIMS), KIMS Foundation and Research Center (KFRC), Hyderabad, India b Center of Medical Genetics, Sir Ganga Ram Hospital,, New Delhi c Amity Institute of Biotechnology, Amity University, Noida, India d Division of Peripheral Vascular & Endovascular Sciences, Medicity Medanta Hospital, New Delhi, India e Department of Cardiac Surgery, Sir Ganga Ram Hospital, New Delhi, India f Department of Neurology, Sir Ganga Ram Hospital, New Delhi, India g Department of Research, Sir Ganga Ram Hospital, New Delhi, India Introduction The quality of anticoagulation therapy and drug toxicity in patients may be measured by different means. The most commonly studied parameters for drug response are the stabilized dose and occurrence of bleeding events. Apart from these, the anticoagulant efﬁciency and risk of toxicity may be calculated by the length of time taken to stabilize, time spent (or percent) within and outside the therapeutic international normalized ratio (INR) range, over anticoagulation (elevated INRs > 3.0 or 4.0), severe over anticoagulation (elevated INRs > 5.0 or 6.0), absolute instability or persistently ﬂuctuating INRs. A wide range of therapy-related clinical factors such as the initiation dose, scheme of dose titration, target INR range, quality and frequency of anticoagulation monitoring and concurrent therapy with inter- acting drugs can contribute to variations in any of the above quality measures. Environmental and demographic causes of variation may be attributed to food intake, body weight and height, age, smoking and alcohol abuse, clinical indication and comorbidities. Most important are the inherent and unvarying variable, i.e. Pharmacological Reports 66 (2014) 243–249 ARTICLE INFO Article history: Received 24 April 2013 Received in revised form 19 August 2013 Accepted 6 September 2013 Available online 3 March 2014 Keywords: Genetic Anticoagulation Acenocoumarol Warfarin India ABSTRACT Aims: The study aims to evaluate the impact of genetic, demographic and clinical data on various measures of outcome of anticoagulation quality in patients. Patients and methods: The study consisted of 310 patients receiving long-term oral anticoagulation therapy in our hospital. Apart from demographic and clinical variables, 21 SNPs (in 7 genes) were analyzed and compared with the outcomes of anticoagulation therapy. Various outcomes that were measured are; supra therapeutic INRs (INR >3, >6), anticoagulation stabilization, time taken to stabilize and proportion of INRs within (2–3), above (>3) and below (<2) therapeutic range. Results: Supra therapeutic INRs were inﬂuenced by CYP2C9*2, *3, CYP4F2 rs2108622, VKORC1-1639G>A, 1173C>T, rs55894764 along with concomitant drugs, smoking, body weight and height. Persistently ﬂuctuating INRs/absolute instability correlated with VKORC1-1639G>A, gender, height and body mass index. The time taken to stabilize was associated with CYP4F2 rs2108622, CYP2C9*14, smoking, clinical indication and concomitant drugs. The overall distribution of INR was inﬂuenced by variants in CYP4F2 rs2108622, CYP2C9*3, rs9332230, VKORC1 1173C>T, 1639G>A, rs55894764, ABCB1 rs2032582, rs1128503, rs1045642 and F5 rs6025, age, smoking and concomitant drugs. Conclusions: Knowledge of factors inﬂuencing the quality of long term anticoagulation can help clinicians to customize therapy either by dose variation, therapy with alternate choice of drug, concurrent heparin therapy and/or frequent INR monitoring. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. Abbreviations: OAC, oral anticoagulant; ADR, adverse drug reaction; BMI, body mass index; SD, standard deviation; CI, conﬁdence interval; BSA, body surface area; INR, international normalized ratio; AOD, arterial occlusive disease; CAD, coronary artery disease; AVR, aortic valve regurgitation; FVL, factor V Leiden; ACE, angiotensin converting enzyme. * Corresponding author. E-mail address: rishanahar@gmail.com (R. Nahar). Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep http://dx.doi.org/10.1016/j.pharep.2013.09.006 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.