Presentation Details
| Accuracy of a Warfarin Clinical Dosing Algorithm Enriched with Genetic Information Compared to the Use of Clinical Algorithm Amr Fahmi1, Ahmed El Bardissy1, Mohamed Saad1, Mohamed Nabil1, Loulia Bader2, Mohamed Kassem1, Ahmed Mahfouz1, Hazem Elewa2. 1Hamad Medical Corporation, Doha, Qatar.2College of Pharmacy, QU Health, Qatar University, Doha, Qatar |
Abstract
Background: Genetic and clinical factors play an important role in warfarin dosing. This is especially important during the initiation phase. Previous research concluded that VKORC1 −1639 G>A (rs9923231), CYP2C9*2 (rs1799853) and *3 (rs1057910) and CYP4F2*3 (rs2108622) could explain more than 40 % of the warfarin dose. On the other hand, clinical factors alone explains 10% of the warfarin dose. A parameter that is widely accepted to evaluate warfarin dosing algorithms is the mean absolute error (MAE) which is the difference between the predicted warfarin dose and the actual dose. Objectives: To identify the impact of CYP2C9*2, *3, VKORC1−1639 G>A and CYP4F2*3 on warfarin dose in an Arab population of mixed nationalities; and to compare the mean absolute error of Gage et al. algorithm when using clinical+genetic factors versus using clinical factors alone. Methods: A cohort of Arab patients newly started on warfarin had their dose calculated using Gage et al. clinical algorithm as published in www.warfarindosing.org . Each patient provided a saliva sample using Oragene Kits. DNA was extracted and samples were genotyped for rs9923231, rs1799853, rs1057910 and rs2108622. Association between genetic variants in VKORC1, CYP2C9, and CYP4F2 and the achieved maintenance dose was tested. MAE was compared between the clinical+genetic and clinical algorithm alone. Results: In our preliminary results, 118 subjects from 12 Arabic countries were recruited. VKORC−1639 G>A, CYP2C9*2, CYP2C9*3 and CYP4F2*3 had a minor allele frequency (MAF) of 0.4, 0.09, 0.07 and 0.35 respectively. Compared to wild type subjects (*1), those with reduced function alleles (*2 or *3) in CYP2C9 required significantly lower warfarin dose (5.6 ± 2.8 mg Vs. 3.7 ± 1.6 mg, p<0.001). With regards to VKORC gene, patients who had the AA allele required significantly lower dose of warfarin compared to those with the AG allele (3.3 ± 1.3 mg Vs. 7.1 ± 3.2 mg, p<0.001), or GG allele (3.3 ± 1.3 mg Vs. 4.7 ± 2.1 mg, p=0.027). CYP4F2 on the other hand had no significant impact on warfarin dose. Dose prediction using the genetic+clinical factors was more accurate compared to the clinical factors alone as shown by lower MAE [1.3 ± 1 mg Vs. 1.9 ± 1.3 mg, p<0.001]. Conclusion: CYP2C9 and VKORC1 variants are important determinants of warfarin dose in the Arab population. The use of the genetic and clinical factors led to better dose estimation when compared to the clinical factors alone.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.