Pharmacogenetics of Cardiovascular Disease

August 7, 2016
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The pharmacogenetics space has expanded to study a wide range of cardiovascular drug classes and has become a mainstream discipline. The classes of pharmacogenetic markers with important clinical application are: 1) pharmacokinetic; 2) pharmacodynamic; and 3) disease mechanisms. Advances in cardiovascular pharmacogenetics have identified markers in each of these classes for a variety of medications that have exhibited improved patient outcomes.

Currently available clinical evidence supports pharmacogenetic testing for certain variants on an individualized basis. Here we will briefly discuss the data for the major genetic variants associated with commonly used cardiovascular drug classes: statins, b-blockers, antiarrhythmics, diuretics, anti-platelet agents and warfarin. We will also highlight the gene variants operative in particular contexts in which pharmacogenetic testing can be implemented by clinicians.

The current velocity of discoveries in genetics has outpaced the production of clinical guidelines. Until the gaps in recommendations are filled, clinicians can decide to target medications to individual patients whose genotypic characteristics indicate that they will benefit from pharmacogenetic testing.01

The main goal of the pharmacogenomics segment of personalized medicine is to have the right person taking the right dose of the right medication. A practical example of the clinical need for pharmacogenomics in cardiovascular practice is the improved ischemic outcomes with the newer platelet P2RY12 receptor inhibitors. This drug subclass also has a well-reported greater risk of adverse events compared to clopidogrel. As such, there is a need in cardiovascular medicine to associate medical therapy with individual patients who will benefit most.

BACKGROUND

A patient cohort’s heterogeneity in medication response is a necessary condition for exploring disease management with pharmacogenetics. The definitions of medication response vary and include such laboratory quantitation as the INR for coumadin, or such clinical endpoints as stent thrombosis for antiplatelet drugs.

Genetic variability can be said to play a causal role in drug response inconsistency when responses follow a familial, heritable pattern, or vary significantly across the ethnic backgrounds of a patient group.

In terms of drug response, there are three broad pharmacological classes of gene variants. These are gene variants that cause 1) pharmacokinetic phenomena, 2) pharmacodynamic processes, and 3) gene variants attendant to the mechanisms contributing to disease. In this synopsis, we consider some common specific drugs applying conventional pharmacogenetic principles.

PLATELET INHIBITION WITH THIENOPYRIDINES

The development of the platelet aggregation inhibitor thienopyridine class has benefited patients with percutaneous coronary intervention and acute coronary syndromes. Despite the clinical benefits, some patients are still at risk for death, stent thrombosis and myocardial infarction. Clopidogrel has received attention as a PGx testing candidate because its effects on platelet function are variable, heritable, and ablated platelet inhibition predicts cardiovascular events. Clopidogrelpharmacogenetic testing focuses on CYP2C19 and ABCB1, the two loci that most affect its pharmacokinetics. Moreover, CYP2C9 and PON1 exert additional pharmacokinetic effects, whileP2RY12 influences response via pharmacodynamic properties, largely attributable to binding affinity.

Clopidogrel effects on platelet function. CYP2C19. Clopidogrel is activated by several enzymes, including CYP2C19, from its inactive form to an active metabolite that selectively and irreversibly inhibits the platelet adenosine diphosphate receptor, P2RY12. The CYP2C19 *2 gene variant is epidemiologically the most common reduced-function (RF) variant exhibiting reduced function of the enzyme.

A patient’s genotype can be identified by the presence of at least 1 RF allele, or by the number of RF alleles, or by the total predicted CYP2C19 enzymatic activity. Carriers of the *2 variant are also known as intermediate metabolizers or poor metabolizers, and produce lower active clopidogrel metabolite concentrations, thereby having reduced platelet inhibition. With respect to clopidogrel metabolism, there exists a predictable gene-dose effect where increasing number of RF alleles is predictive of the magnitude of reduction of platelet inhibition. Patients who carry the gene variant *17 are ultrametabolizers and exhibit markedly increased CYP2C19 enzyme activity. These people produce more active clopidgrel metabolite, and respond with greater platelet inhibition.

Dosing adjustments with clopidogrel only partly overcome the metabolic effects of the *2 variant. Therefore, these patients continue to carry at least somewhat greater risk for cardiovascular events. Antithetically, ticagrelor, prasugrel and ticlopidine, produce more uniform platelet inhibition in both *2 gene variant carriers as well as in noncarriers of the *2 variant.

CYP2C19 and clopidogrel response. The CYP2C192 gene variant allele is associated with a graded risk of death, MI, or stroke that parallels the reported platelet function data. Patients who are intermediate metabolizers carry 1 allele and have a 1.5-fold increased risk, while poor metabolizers carry 2 alleles and have a 1.8-fold increase in cardiovascular risk with clopidogrel therapy. This risk pattern is also present for stent thrombosis, with a 2.6-fold and 4-fold increased risk in patients with 1 and 2 CYP2C192 variant alleles, respectively. In view of these reports, the genetic associations between CYP2C19*2 and platelet quality are illustrated in clopidogrel’s response pertaining to PCI.

In fact, the Food and Drug Administration’s initiative to include pharmacogenetic information for medication guidance was inspired largely by the research observations for clopidogrel. Moreover, the CYP2C19 gene variant 17 that is associated with increased enzyme function increases bleeding risk , and confers defense against ischemic events. Conversely, patients carrying the lower enzyme function gene variant CYP2C192 do not show a greater risk of cardiovascular mortality, stroke, MI, or stent thrombosis when treated with prasugrel or ticagrelor.

The ABCB1 Transporter. The ABCB1 gene is a member of the ATP-binding cassette and encodes an apical transmembrane protein in both enterocytes and hepatocytes that functions to reduce bioavailability.

For patients treated with clopidogrel there is an increased risk for mortality, MI, or stroke in carriers of two copies of the ABCB1 T-T-T gene variant compared to patients who carried no copies. These observations correspond to the data reported for platelet function. Similarly, sub-functional gene variation at the ABCB1 locus does not appear to influence patients treated with prasugrel or ticagrelor.

Clinical inferences. There is a strong and consistent association between the CYP2C192 gene variant and a greater risk for cardiovascular events in patients undergoing PCI in acute coronary syndromes who are treated with clopidogrel. Other antiplatelet agents such as prasugrel and ticagrelor lessen the adverse risk of these events associated with CYP2C192. The commercial availability of CYP2C19 genotyping along with strong evidence to support physicians choosing to perform CYP2C19*2 testing has important clinical implications. First, PGx testing is demonstrably beneficial in patients who have had such complications from clopidogrel therapy as stent thrombosis. Second, gene testing is beneficial in the clinical scenario in which the physician wants a more informed choice of dual antiplatelet therapy around the PCI period. Lastly, PGx testing for CYP2C19 is clinically instructive for special populations for which exists significant perturbation of physiologic metabolism including diabetic patients, those having ST elevation MI, patients with a history of cerebrovascular disease and patients older than 75 years.

On the basis of currently available studies, patients who are poor metabolizers at the CYP2C19locus, should be offered antiplatelet therapy other than clopidogrel. This strategy is preferable to simply increasing clopidogrel dose, because the latter has not demonstrated clinical benefit over clopidogrel at conventional dose. Perhaps the most difficult group to treat is the intermediate metabolizers, patients who carry 1 low function CYP2C19. It is for this group that consideration of such additional clinical risk factors as diabetes mellitus, bleeding risk, thrombosis risk factors and body mass index must be carefully considered to better determine therapy.

STATINS AND HMGCoA INHIBITION

Medications in the “statin” drug class inhibit the hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). These medications produce at least four types of effects. First, they lower circulating low-density lipoprotein cholesterol (LDLc). Second, they have been shown to impart lower mortality from cardiovascular events in a variety of landmark clinical studies. Third, statins are known to produce musculoskeletal side effects including life-threatening rhabdomyolysis. Fourth, the often frustrating problem of genetically-affected statin drug adherence.

LDLc reduction. While most patients treated with statins respond within a range of 30% to 50% LDLc reduction, the clinical challenge rests in the real-world variation that can be as wide 10% to 70%. HMGCR and APOE represent the two gene loci that categorically affect LDLc reduction.

The APOE gene. The APOE haplotypes associated with anti-lipidemic, cognitive, and thromboembolic phenotypic characteristics are e2, e3 and e4. These haplotypes are produced by the APOE gene variants rs7412 and rs429358. In terms of LDLc reduction, carriers of e2 present the greatest effect, then carriers of the e3 variant, while e4 variant haplotype carriers exhibit the least LDLc reduction. APOE haplotypes predictably affect a variety of statin molecules resulting in low but significant – generally <15% – dilutions of circulating LDL cholesterol.

The HMGCR gene. A minor haplotype defined by four reported SNPs of HMGCR, impart a 5% to 20% reduction in LDLc via pravastatin or simvastatin caused by a variant HMGCR splicing that produces a less statin-sensitive form of the HMGCR enzyme.

Reduction in cardiovascular events. Cardiovascular disease prevention by statins is mediated via LDLc reduction, though examples in the drug class display a wide range of well-documented clinically useful metabolic effects. Among the scarce genetic predictors of these effects is the rs20455 SNP. This SNP is found in the kinesin-like protein 6 (KIF6) gene and may represent a candidate for disease mechanism. The clinically relevant notion for this gene is that carriers exhibit a greater benefit from statin therapy compared to noncarriers with such markers as triglycerides, C-reactive protein remaining equal. Despite the uncertainty produced by equivocal genome-wide meta-analysis for coronary artery disease of large randomized placebo-controlled statin trials the gene variant remains a focus of attention among workers in the field.

Statin-induced adverse events. Though infrequently encountered, the statin-induced risk of such musculoskeletal adverse events as rhabdomyolysis is a point clinical interest. The safety profile of statins drugs has been long studied and well-defined. It appears that the greatest role in the generation of adverse events is played by the hepatic transporter SLCO1B1, while the hepatic CYP drug-metabolizing enzyme variants do not seem to affect statin-induced adverse event risk.

Statin transporter SLCO1B1. Among the many gene variants of the the solute carrier organic anion transporter family, member 1B1 gene (SLCO1B1), the *5 variant disrupts the normal localization of this protein to the hepatocyte cell membrane. This leads to higher plasma statin concentrations and, conversely, lower intracellular statin. Consequently, carriers of *5 are at 400%-500% increased risk of severe, creatine kinase-positive simvastatin-induced myopathy and 200%-300% increased risk of creatine kinase-negative myopathy.

The observed risk for myopathy with the *5 gene variant depends on the specific statin, and in order of increasing risk it is: rosuvastatin or fluvastatin, pravastatin, atorvastatin and simvastatin. Moreover, the plasma concentration effects mirror the *5 variant’s influence on statin clearance.

Statin therapy is most beneficial when the drug is continued chronically. Unfortunately, optimal outcomes are hampered by patient nonadherence to statin therapy. It has been reported that patients carrying the SLCO1B1*5 allele have a higher rate of statin nonadherence compared to non-carriers. As such, there seems to be a genetic basis to statin nonadherence that can be exploited clinically.

Although magnitude of associations for genotyping and statin efficacy is relatively small – on the order of 10-15% differences in LDLc reduction, statin-induced side effects and nonadherence are more variable and much less foreseeable.

The combination of genetic testing for APOEHMGCR and SLCO1B1 may, along with standard testing for drug-metabolizing genes, offer opportunities in identifying gene variants that can aid providers to deliver the greatest therapeutic benefit with the lowest foreseeable risk.

Genetic variability can be said to play a causal role in drug response inconsistency when responses follow a familial, heritable pattern, or vary significantly across the ethnic backgrounds of a patient group. In terms of drug response, there are three broad pharmacological classes of gene variants. These are gene variants that cause 1) pharmacokinetic phenomena, 2) pharmacodynamic processes, and 3) gene variants attendant to the mechanisms contributing to disease. In this synopsis, we consider some common specific drugs applying conventional pharmacogenetic principles.

DIURETICS

Hemodynamic response. The adducin 1a gene ADD1 contributes to underlying hemodynamic disease. The gene is known to handle sodium load. Patients carrying the Gly460Trp substitution are more sensitive to volume:Nafluxuation and are more responsive to thiazide diuretics for blood pressure lowering.

Studies with respect to ADD1 and clinical outcomes have to date not been consistent. In one report, patients carrying the ADD1 Trp460 variant had more protection from MI and stroke than patients with the Gly460 gene variant when treated with thiazides. However, this difference in the cardioprotective effects of diuretics was not be reproduced in subsequent larger studies.

BETA-BLOCKERS

Drugs in the beta-blocker class antagonize the beta-1 adrenergic receptor which is encoded by theADBR1 gene. Genes controlling beta-blocker pharmacology include CYP2D6 which regulates the pharmacokinetics of the drug class, and the genes ADRB1, ADRB2, and GRK5 which modulate beta-blocker pharmacodynamics. Consequently, these genes regulate such hemodynamic effects as heart rate, blood pressure and left ventricular ejection fraction, the disturbance of which contributes to such clinical outcomes as death, heart failure and MI.

Effects and CYP2D6 Variants. Beta-blockers, along with around 25% of drugs currently in clinical use are substrates for CYP. There is substantial metabolic variation even within the beta-blocker class. For example, metoprolol is extensively metabolized by the hepatic CYP2D6 monoxidase. Conversely, such beta-blocker examples as atenolol and carvedilol are not inactivated by CYP2D6. The most common gene variant CYP2D64 results in complete ablation of CYP2D6 enzyme activity. Patients carrying the CYP2D64 gene variant have a higher systemic metoprolol concentration. This translates into a greater reduction in HR and BP.

Significant ADRB1 gene variants. The long observed differences in dose response for propranolol among various ethnicities prompted the exploration into the influence of genotype on beta-blocker pharmacodynamics. The ADBR1 gene variant Ser49Gly causes lower down-regulation of the receptor. Similarly, the ADBR1 Arg389Gly gene variant causes greater signal transduction intensity. The net effect of carrying either allele, therefore, is that patients experience a more active and sensitive beta-1-receptor. Additionally, it has been observed that patients carrying 2 alleles of the Arg89 gene variant achieve lower HR and BP in response to metoprolol, although this effect is not achieved across all other beta-blockers.

Moreover, with respect to heart failure, patients carrying 2 alleles of the the ADBR1 Arg389 gene variant with existing systolic heart failure who were treated with either carvedilol or metoprolol, but not bucindolol, had significantly greater improvements in LVEF compared to patients carrying theADBR1 Gly389 gene variant.

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