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

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188 Applying Pharmacogenomics in Therapeuticsto aspirin is a complex phenotype involving multiple genes and molecular pathways.Aspirin response phenotypes can be categorized as directly or indirectly related toCOX-1 activity, with phenotypic variation indirectly related to COX-1 being muchmore prominent. Recent data indicate that variability in platelet response to aspirinis genetically determined, but the specific gene variants that contribute to phenotypicvariation are not known.STATINSHydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors competitivelyinhibit the enzyme HMG-CoA reductase. HMG-CoA reductase is the rate-limitinghepatic enzyme responsible for converting HMG-CoA to mevalonate, which is aprecursor of cholesterol. HMG-CoA reductase inhibitors decrease LDL concentrationsby reducing hepatic cholesterol production and increasing LDL clearancefrom the blood. The persistent inhibition of cholesterol synthesis in the liver alsodecreases concentrations of very low density lipoproteins. 32 In addition, HMG-CoA reductase inhibitors increase HDL concentrations and decrease triglycerideconcentrations. 32 The reduction in triglyceride concentrations may be throughhepatic synthesis inhibition and lipoprotein lipase activity enhancement in adipocytes.In addition to specific lipoprotein effects, HMG-CoA reductase inhibitorshave been shown to halt the progression and facilitate the regression of atheroscleroticlesions.The potential value of statin pharmacogenetic information include identificationof genes and genetic variants that influence statin responsiveness, whichholds promise for identifying molecular components of physiological lipid andinflammatory pathways that mediate statin effects. However, the most importantclinical benefits of statin pharmacogenetic knowledge would be based on identifyinga set of genotypes that aid in predicting the outcomes of statin treatmentin terms of reduced risk for cardiovascular events, together with reduced risk forserious ADRs.Statins are among the most widely used medications and are largely safe andwell tolerated. Nevertheless, myopathy is the most common side effect of statins,with symptoms ranging from mild myalgias without creatine kinase (CK) elevationto life-threatening rhabdomyolysis with markedly elevated CK levels, muscledamage, and acute renal injury. The risk for statin-induced myopathy is greaterwith higher statin doses or inhibition of statin metabolism or clearance due todrug interactions or decreased hepatic or renal function. 32 In addition, there is aheritable component to the risk for statin-induced myopathy. The strongest data inthis regard exist for the solute carrier organic anion transporter family, member1B1 (SLCO1B1) gene. This gene encodes the organic anion transporting polypeptide(OATP) 1B1, which transports most statins, with the exception of fluvastatin,to the liver. SLCO1B1 genotype exerts a large effect on risk for simvastatinmyotoxicity.Current studies that identify genomics of LDL response are also a key step inaddressing the broader question of whether genomic markers identify subjects whodevelop coronary events during statin therapy.
Drug Therapy of Cardiovascular Diseases189Clinical ApplicationA number of large randomized controlled trials have demonstrated significant reductionsin coronary events and stroke with statin therapy for both primary and secondaryprevention of CVD. 33β-BLOCKERSBeta-adrenergic receptor antagonists (β-blockers) are an important class of cardiovasculardrugs used for a range of conditions including cardiac arrhythmias, ACS,stable angina, hypertension, and heart failure. β-Blockers antagonize endogenouscatecholamines at β-adrenergic receptors, of which two subtypes, β1 and β2, aremost important for cardiovascular pharmacology. 34 Important autoregulatory mechanismsinclude G-protein-coupled receptor kinases (GRKs); enzymes that moderatesignaling through phosphorylation of activated β-receptors; and presynaptic α2Cadrenergicreceptors (ADRA2C), which regulate norepinephrine release via a negativefeedback pathway. 35Two of the most commonly used β-blockers in heart failure, metoprolol andcarvedilol, both undergo substantial metabolism by the highly polymorphicCYP2D6 enzyme, whose gene contains loss of function, deletion, and duplicationpolymorphisms. The pharmacokinetics of these drugs is affected based on CYP2D6genotype; however, there is less evidence for differences in efficacy or side effects. 36There are also a number of studies suggesting functional polymorphisms inadrenergic receptor signaling genes are associated with differential response toβ-blockers, particularly in hypertension and heart failure. The genes with the strongestdata are ADRB1, ADRA2C, GRK5, and GRK43. 37 These data suggest differentialresponses to β-blockers by genotype that includes blood pressure response,improvement in left ventricular ejection fraction (LVEF), and survival differences inhypertension and heart failure.A large prospective randomized pharmacogenomics trial PEAR (PharmacogenomicEvaluation of Antihypertensive Responses) used genome-wide association studies(GWASs) genotyping to determine the relationship between genetic polymorphismsand antihypertensive medications. Atenolol, hydrochlorothiazide (HCTZ) as well as acombination of the two were studied. It was found that participants who had the T/Tand T/C genotypes of the intergenic SNP rs1458038 near FGF5 had a better responseto atenolol compared to those who had the C/C genotype. The study concluded thatwhite Caucasian hypertensive individuals with the risk allele for HTN(T) might have abetter response to atenolol compared to HCTZ. This gene might be used in the futureas a marker for high sympathetic nervous system and renin–angiotensin activity. 38,39Clinical ApplicationEven though the pharmacogenetic data for β-blockers have not yet been significant towarrant clinical utility, they are the next closest examples among the cardiovasculardrugs that solidify clinical application of pharmacogenomics. Currently, investigationsare looking at the benefits of β-blocker therapy for some subjects with heart failure.
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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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Concepts in Pharmacogenomics and Pe
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2Principles ofPharmacogeneticBiotec
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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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