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

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192 Applying Pharmacogenomics in TherapeuticsOne study showed that three SNPs in the CACNA1C gene had a significant impactin lowering BP with CCBs. 54 In addition, the effects of CYP3A5*3 and *6 variantson verapamil treatment for hypertension risk outcomes in blacks and Hispanicswere studied. 55 Individuals that are homozygous for the T allele of NPPA T2238Chad more favorable clinical outcomes when treated with a CCB, whereas C carriersresponded better to a diuretic. 52 Carriers of the β-adrenergic receptor 1 (BADRB1)Ser49–Arg389 haplotype carriers had higher death rates compared to those with otherhaplotypes when treated with verapamil. 56The majority of studies looking at CCBs have focused on calcium-signalinggenes, such as CACNA1C, CACNB2, and KCNMB1. Although CACNB2 has beenreported as a hypertension gene in GWASs, it is evident that further studies are stillneeded to confirm genetic associations in CCB response. 57ANTIARRHYTHMICSDuring the past two decades, pharmaceutical companies have been faced with thewithdrawal of some of their marketed drugs because of rare, yet lethal, post marketingreports associated with ventricular arrhythmias. The implicated drugs includeantiarrhythmics, noncardiac drugs, such as antibiotics, histamine blockers, and antipsychotics.DNA variants underlie not only variability in cardiac rhythm but also theresponse of normal and abnormal cardiac rhythms to drug exposure. These undesiredeffects include prolongation of the QT interval, which may lead to characteristicventricular tachyarrhythmias, known as torsades de pointes (TdP). These clinicalsymptoms of the acquired long QT syndrome (LQTS) are also found in an inheritedform of the disease, called congenital LQTS.Currently, a number of environmental (nongenetic) and genetic risk factors foracquired LQTS have been described. Nongenetic factors include female gender,hypokalemia, and other heart diseases. The knowledge of genetic risk factors isemerging rapidly. During the last decade, mutations in several genes encodingion channels have been shown to cause congenital LQTS. In acquired LQTS,a number of “silent” mutations in these LQTS genes have been identified, andfunctional polymorphisms in the same genes have been found to be associatedwith an increased vulnerability for the disease. Furthermore, there is also evidencethat interindividual differences in drug metabolism, caused by functionalpolymorphisms in drug-metabolizing enzyme genes, may be a risk factor foracquired LQTS, especially if multiple drugs are involved. This review evaluatesthe current knowledge on these risk factors for acquired LQTS, with an emphasison the genetic risk factors. It also assesses the potential to develop pharmacogenetictests that will enable clinicians and pharmaceutical companies to identifyat an early stage patients or individuals in the general population who are at riskof acquired LQTS. 58Congenital LQTS is a rare genetic disease with discernible prolongation of the QTinterval. Other signs and symptoms seen with LQTS are recurrent syncope, palpitations,seizures, and the development of TdP that can lead to sudden death. TdP is morphologicallydistinctive since affected individuals may develop polymorphic ventriculartachycardia. 59 On the other hand, similar LQTS features are present due to certain
Drug Therapy of Cardiovascular Diseases193drug’s adverse effects, termed drug-induced LQTS (diLQTS). Antiarrhythmic drugsthat commonly cause LQTS are sotalol, dofetilide, or quinidine.diLQTS is more likely associated with lower, rather than high doses of quinidine.This could be in part due to mechanism of quinidine where at low doses it producesarrhythmogenic effects on cardiac repolarization. However, quinidine inhibitsrepolarization-related arrhythmias at higher doses. 58 The genes that cause patients tobe at a higher risk for diLQTS have not been fully identified. Some studies have associatedallele variants of IKs (slow rectifier potassium channels) 45 with an increasedsusceptibility to drug-induced TdP. 39 Others have found women to be at a greater riskfor developing diLQTS due to the difference in modulation of IKr (rapid rectifierpotassium channels). 39Clinical ApplicationIdentifying patients at risk for long QT-related arrhythmias during drug therapy maybecome possible as platforms to identify both common and rare variants are increasinglydeployed. Early studies suggest that available atrial fibrillation therapies maybe less effective in some genetically defined subsets, and these patients thus may becandidates for alternate approaches.N-ACETYLTRANSFERASEThe acetylation polymorphism elucidates another genetic polymorphism of a drugmetabolizingenzyme studied in the early period of pharmacogenetics. NAT, aphase II conjugating liver enzyme, catalyzes the N-acetylation and O-acetylation ofarylamine carcinogens and heterocyclic amines. The slow acetylator phenotype oftenexperiences toxicity from drugs such as procainamide and hydralazine, whereasthe fast acetylator phenotype may not respond to hydralazine. Slow acetylators arealso at risk for sulfonamide-induced toxicity and can suffer from idiopathic lupuserythematosus while taking procainamide. 60 The slow acetylator phenotype is anautosomal recessive trait. Studies have shown large variations of the slow acetylatorphenotype among ethnic groups. Allelic variation at the NAT2 gene locus accountsfor the polymorphism seen with acetylation of substrate drugs.CONCLUSION AND FUTURE PERSPECTIVESTranslating fundamental discovery in genome science to individual patients andpopulations is a challenge for the field, and genotyping for selection of appropriatedrug therapy is one of the first ways this is being accomplished. In oncology,tumor genotyping is rapidly becoming standard of care to identify specific mutationsthat then dictate selection of therapy. 61 Pre-prescription germline genotypingis becoming standard of care to reduce the risk of serious adverse reactionsto carbamazepine and abacavir. 62 In cardiovascular therapy, a number of centersare now deploying programs to use CYP2C19 genotypes to guide clopidogreltherapy. The National Institutes of Health is making major investments in discoveryof new pharmacogenomic pathways and in how that information can be
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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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11 PharmacoeconogenomicsA Good Marr
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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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