AUTHOR=Roco Angela , Nieto Elena , Suárez Marcelo , Rojo Mario , Bertoglia Maria Paz , Verón Gabriel , Tamayo Francisca , Arredondo Annabella , Cruz Daniela , Muñoz Jessica , Bravo Gabriela , Salas Patricio , Mejías Fanny , Godoy Gerald , Véliz Paulo , Quiñones Luis Abel 

TITLE=A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00325

DOI=10.3389/fphar.2020.00325

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables.</p></sec><sec><title>Objective</title><p>The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients</p></sec><sec><title>Methodology</title><p>DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0–3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for <italic>VKORC1</italic> (<italic>rs9923231</italic>), <italic>VKORC1</italic> (<italic>rs7294</italic>), <italic>GGCx</italic> (<italic>rs11676382</italic>)<italic>, CYP4F2</italic> (<italic>rs2108622</italic>)<italic>, ABCB1</italic> (<italic>rs1045642</italic>)<italic>, CYP2C9*2</italic> (<italic>rs1799853</italic>), <italic>ApoE</italic> (<italic>rs429358</italic>), and <italic>CYP2C9*3</italic> (<italic>rs1057910</italic>).</p></sec><sec><title>Results</title><p>The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were <italic>VKORC1</italic> (<italic>rs9923231</italic>), <italic>CYP2C9*2</italic> (<italic>rs1799853</italic>), and <italic>CYP2C9*3</italic> (<italic>rs1057910</italic>), explaining for another 37% of the variability.</p></sec><sec><title>Conclusion</title><p>We developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included <italic>VKORC1</italic>, <italic>CYP2C9*2</italic>, and <italic>CYP2C9*3</italic> polymorphisms, as well as age, sex, BMI, and initial INR.</p></sec>