Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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184 Applying Pharmacogenomics in TherapeuticsTABLE 7.1Examples of Cardiovascular Drugs with Evidence ofRelationship between Genetics and Efficacy or ToxicityDrug/Drug Classβ-Agonistsβ-BlockersACEIsAntiarrhythmicsP2Y12 blockersAbciximabAspirinHeparinWarfarinARBsDigoxinDiureticsHydralazineLipid-lowering drugsStatinsGemfibrozilABRB2Gene(s) Associated withEfficacy or Toxicity aADRB1ACEGs protein α subunitCYP2D6ACEAGTAT 1 receptorBradykinin B 2Congenital LQTS-associated genesNAT2 (procainamide)CYP2D6Platelet P2Y12 receptorPlatelet glycoprotein IIIaCOX1Platelet Fc receptorCYP2C9, VKORC1AT 1 receptorP-glycoproteinG protein B 3 subunitADD1NAT2ApoECholesteryl ester transfer proteinStromelysin-1β-fibrinogen LDL receptorLipoprotein lipaseACEApoEStromelysin-1Source: From Johnson J, et al., Clin Pharmacol Therap, 90, 519–531, 2011.aThe reader is referred to focused reviews for detailed information asdescribed elsewhere.The VKORC1 gene encodes the vitamin K epoxide reductase enzyme. Warfarinexerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, which catalyzesthe conversion of vitamin K epoxide to vitamin K. Vitamin K is an essentialcofactor in the synthesis of several clotting factors. A common noncoding variant,−1639G>A, is associated with an increased sensitivity to warfarin. 5 Patients who
Drug Therapy of Cardiovascular Diseases185carry the −1639G>A polymorphism in the promoter region of the VKORC1 gene aremore sensitive to warfarin and require lower doses.Polymorphisms in CYP2C9 and VKORC1 account for approximately 40% ofthe variance in warfarin dose. 6 Current warfarin labeling suggests lower doses forpatients with certain genetic variations. Patients with the CYP 2C9*2 and CYP2C9*3 alleles need lower warfarin maintenance doses than patients with the wildtypeallele in order to achieve their desired international normalized ratio (INR).The two allelic variants will result in slower metabolism of warfarin. Additionally,VKORC1 (vitamin K epoxide reductase A1) haplotype necessitates a lower warfarinmaintenance dose due to decreased expression of the messenger RNA responsiblefor production of proteins necessary for VKORC1 enzyme formation. 7Prospective randomized clinical trials are currently underway utilizing dosingalgorithms that incorporate genetic polymorphisms in CYP2C9 and VKORC1 todetermine warfarin dosages. 6 FDA-approved testing for VKORC1 and CYP2C9 variantsis available for patients on warfarin. Variations, such as missense mutationsin the gene encoding for VKORC1, cause warfarin resistance. Hence, the patient’sgenotypic variance in the two enzymes predicts response to warfarin therapy and theamount of warfarin dose needed. 8Clinical ApplicationProspective randomized clinical trials are currently underway employing dosingalgorithms that incorporate genetic polymorphisms in CYP2C9 and VKORC1 todetermine warfarin dosages. Variations of the VKORC1 gene that might require anadjustment in the dose of warfarin occur in up to 89% of Asians and in about onethirdof Caucasians and African Americans. More than one in ten Caucasians has arelevant variation in CYP2C9, and the variation is less common in non-Caucasians. 9When these genetic variations are known, warfarin can be initiated at a higher orlower dose as appropriate. The warfarin dose calculator at www.warfarindosing.org can also take these variations into consideration when they are known. In addition,the dosing calculator uses clinical factors, such as drug–drug interactions, age,weight, for determining dose.At present, available genotype-guided warfarin initiation dosing algorithmsshow limited clinical validity and utility compared with standard therapy, especiallyfor patients who are dosed based on their clinical information and close INRmonitoring. 10 A study with high dropout rate, which used CYP2C9 only to determinedosing, has shown some benefit on anticoagulation control with minor bleedingevents. 11 An observational study reported a relationship between providing warfaringenetic information to clinicians and reduced hospitalizations. 12Other anticoagulants of minor pharmacogenomic interest include heparin, dabigatran,rivaroxaban, and apixaban. Dabigatran was approved by the FDA in October2010 for prevention of stroke and blood clots in people with atrial fibrillation.Rivaroxaban was approved in November 2011 to treat atrial fibrillation and lowerthe risk of blood clots after hip and knee replacements. Apixaban was approved inDecember 2012 to lower the risk of stroke and dangerous blood clots in patients withatrial fibrillation.
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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1Concepts inPharmacogenomics andPer
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11 PharmacoeconogenomicsA Good Marr
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Pharmacoeconomics of Pharmacogenomi
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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