A systematic review on pharmacogenetics in cardiovascular disease

REVIEW

Controversies in cardiovascular medicine

A systematic review on pharmacogeneticsin cardiovascular disease: is it ready forclinical application?Jeffrey J.W. Verschuren1, Stella Trompet1,2, Judith A.M. Wessels3,Henk-Jan Guchelaar3, Moniek P.M. de Maat4, Maarten L. Simoons5,and J. Wouter Jukema1,6,7*

1Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; 2Department of Geriatrics and Gerontology, Leiden UniversityMedical Center, Leiden, The Netherlands; 3Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands; 4Department ofHematology, Erasmus Medical Center, Rotterdam, The Netherlands; 5Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands; 6Durrer Center forCardiogenetic Research, Amsterdam, The Netherlands; and 7The Interuniversity Cardiology Institute (ICIN), Utrecht, The Netherlands

Received 16 March 2011; revised 20 June 2011; accepted 27 June 2011; online publish-ahead-of-print 30 July 2011

Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important appli-cation of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions.Many studies focusing on drug–gene interactions have been published in recent years, some of which led to adaptation of FDA recommen-dations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides acomprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of car-diovascular diseases.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Pharmacogenetics † Single-nucleotide polymorphism † Drug therapy † Drug response † Cardiovascular

disease † Systematic review

IntroductionPharmacogenetic studies search for heritable genetic polymorph-isms that influence responses to drug therapy. Pharmacogeneticshas many possible applications in cardiovascular pharmacotherapyincluding screening for polymorphisms to choose agents with thegreatest potential for efficacy and least risk of toxicity. Pharmaco-genetics also informs dose adaptations for specific drugs inpatients with aberrant metabolism.

Each year, an estimated 785 000 Americans suffer a myocardialinfarction (MI) and 610 000 people experience a new stroke.Despite advances in management, 470 000 recurrent MIs and185 000 recurrent strokes occur annually.1 The numbers fromEurope are not much better, indicating the importance of opti-mizing treatment strategies.2

Although several reviews on pharmacogenetics in cardiologyhave been published, most focused on specific drug subgroups.This systematic review offers a comprehensive summary of thecurrent knowledge of pharmacogenetics in cardiology, elaborateson progress towards individualized drug therapy, and incorporatesconclusions made during the Colloquium ‘Pharmacogenetics ofcardiovascular drugs: implications for a safer and more efficientdrug therapy’ held by the Royal Netherlands Academy of Artsand Sciences in October 2010. In particular, the review considersthe most relevant and well-studied polygenic markers for somepressing clinical issues: (i) statins: focusing on variability in efficacyand risk of myopathy; (ii) resistance to antiplatelet medication; (iii)dosing issues with oral anticoagulants; (iv) suboptimal responses tob-blockers; and (v) the variable response in blood pressure and

* Corresponding author. Tel: +31 71 526 20 20, Fax: +31 71 526 68 85, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected]

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clinical events in patients taking angiotensin-converting enzyme(ACE)-inhibitors (Table 1).

MethodsRelevant articles were identified by searching MEDLINE using the fol-lowing keywords and Medical Subject Headings (MeSH) terms: phar-macogenetics, genetic heterogeneity, genetic polymorphism, singlenucleotide polymorphism (SNP), haplotypes, treatment outcome,adverse effects, drug therapy, cardiovascular diseases (CVDs), and/orcoronary disease. We screened the title and abstract of possibly rel-evant citations and retrieved, if potentially interesting, full reports orabstracts. We checked the references of retrieved publications foradditional relevant papers and included all available literature untilMay 2011. We excluded reviews, editorials, and articles in languagesother than English.

Statins: variability in efficacy andrisk of myopathyStatins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibi-tors, are widely prescribed to lower plasma cholesterol levels,thereby reducing cardiovascular risk. Despite the clinical effective-ness of statins, proven in large randomized controlled trials,3,4 inter-individual variation in response means that many patients fail toachieve adequate reduction in cholesterol levels even after multiple-dose adjustments.5 Genetic factors are thought to be partly respon-sible for this inter-individual variation. Indeed, more than 40 candi-date genes have been described with respect to the differentialeffect of statins in decreasing the risk of clinical endpoints includingcardiovascular death, MI, and lipid-lowering abilities (see Supplemen-tary material online, Table S1).

Variability in lipid loweringSeveral pharmacogenetic studies examined the gene encoding thecholesterol ester transfer protein (CETP) involved in cholesterolmetabolism and, in particular, the TaqIB variant (rs708272). Initialstudies associated the B2B2 genotype with lower CETP levels,6

higher high density lipoprotein cholesterol (HDL-C) levels, andlower risk of progression of coronary artery disease (CAD),

compared with the B1B1 genotype.7– 11 However, on statin treat-ment, B1B1 patients showed lower progression of CAD than B2B2carriers. A meta-analysis confirmed the firm association betweenTaqIB and HDL-C levels and CAD risk, while no significant inter-action between this polymorphism and pravastatin treatmentcould be demonstrated.12 This meta-analysis included studies thatenrolled patients with and without a history of CAD. In contrast,the original study included only patients with significant CAD.7 Fur-thermore, long-term results from the Regression Growth EvaluationStatin Study (REGRESS), the first study to report the possible phar-macogenetic interactions between the CETP polymorphism andstatin treatment,13 also contrast with the meta-analysis. REGRESSdemonstrated significantly higher 10-year mortality in statin-treatedmale patients carrying the B2 allele, compared with the B1B1 geno-type.14 Therefore, although untreated B2B2 patients have a lowerrisk of CAD progression, statin treatment is more beneficial inpatients with the B1B1 genotype, negating the initial advantage ofthe B2 allele in CAD.

The extensive studies of apolipoprotein E (APOE), and in particu-lar the 12/13/14 variants defined by combinations of two poly-morphisms (Cys112Arg, rs429358 and Arg158Cys, rs7412) areequivocal.15 Several studies report an association between 12 car-riers and an increased lipid-lowering response to statins orreduced cardiovascular outcomes, such as non-fatal MI andcardiovascular-related mortality, whereas other studies did notfind significant associations.16 Although the first genome-wideassociation study (GWAS) on statin effects showed a significantassociation between the three APOE polymorphisms and the low-density lipoprotein cholesterol (LDL-C) response,17 a recentmeta-analysis did not confirm this association.18 Therefore, itseems unlikely that a true association exists between APOE poly-morphisms and the lipid-lowering response to statin treatment.

Since most studies discussed so far had insufficient power todetect the small effect produced by individual genetic loci,Barber et al.19 combined three statin GWASs encompassing3936 patients. Carriers of a polymorphism (rs8014194) in thecalmin (CLMN) gene on chromosome 14 had a significantlygreater reduction of 3% in total cholesterol compared with non-carriers. The exact function of calmin is unknown, but it containsa calponin domain expected to have actin-binding activity20 andis strongly expressed by the liver and adipose tissue.21 Neverthe-less, this polymorphism explained only 1% of the variability instatin response.19 A SNP near APOE, in the APOC1 gene(rs4420638), showed moderate evidence for being associatedwith statin-induced LDL-C changes. Most other putative associ-ations appeared to be independent of statin treatment and werein loci previously associated with lipid or lipoprotein traits.19

Kinesin-like protein 6 and variability inclinical outcomeNext, carriers of the arginine-coding allele (rs20455) of kinesin-likeprotein 6 (KIF6) showed a substantially higher benefit with pravas-tatin treatment compared with non-carriers in three large clinicaltrials, which appeared to be independent from lipid- and C-reactiveprotein-lowering effects.22– 24 Kinesin-like protein 6 is a member ofthe molecular motor superfamily involved in the intracellular

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Table 1 Major issues in cardiovascular drugpharmacogenetics and the strength of the geneticevidence

Drug class Problem Evidence

Statins Variable lipid lowering MediocreRisk of myopathy Strong

Antiplateletdrugs

Resistance Strong

Anticoagulants Dosing problems Strong

b-Blockers Variable response Poor

ACE-inhibitors Variable blood pressure reduction MediocreVariable benefit to decrease risk of

eventsMediocre

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transport of several important molecules, including mRNA.25 Arecent meta-analysis of 19 studies (in total 17 000 CAD casesand 39 369 controls) concluded that the SNP in question wasnot associated with the risk of CAD.26 This study was, however,unable to explore the effect of statins, since this information wasnot available for all included studies, but the probability of astrong influence on the effect of statin decreases with this publi-cation. Nevertheless, further (functional) studies are needed toexplore the role of KIF6.

Risk of myopathyGenetic variations are also associated with an altered risk ofadverse drug reactions (ADRs), especially statin-induced myopa-thy. The incidences of myopathy and rhabdomyolysis are estimatedat 11.0 and 3.4 per 100 000 person-years, respectively. The casemortality rate with rhabdomyolysis is 10%.27

The polypeptide organic anion transporter P1B1 (OATP1B1)encoded by the SLCO1B1 gene is involved in the hepatic uptakeof statins.28,29 Two common polymorphisms (521T . C,rs4149056 and 388A . G, rs2306283) influence the transporterfunction of OATP1B1,30 markedly altering statin pharmacoki-netics.31 A GWAS showed a strong association between a non-coding polymorphism (rs4363657) and statin-induced myopathyin patients treated with high-dose simvastatin.32 This polymorph-ism is in almost complete linkage disequilibrium (R2¼ 0.97) withthe 521T . C polymorphism and was expressed by more than60% of patients who developed myopathy with an odds ratio of4.7 per copy of the C allele.32 A subsequent study confirmedthis pharmacogenetic effect in simvastatin-induced myopathy,33

but not with either atorvastatin or pravastatin,33 probably indicat-ing a simvastatin specific effect.34

In conclusion, the reports on genetic variability and response tostatin treatment are difficult to interpret. Variability in studydesigns and endpoint definitions probably contribute to thesemixed results. Since statins’ full pharmacodynamic spectrum,besides their lipid-lowering properties, remains largely unknown, itis not surprising that clear cut pharmacogenetic results are lacking.It is likely that future research will further elucidate statins’ exactmechanisms of action and help explain the variability in response.Newly identified loci influencing lipid concentration identified inrecent GWAS might also prove to have pharmacogenetic associ-ations with statin treatment.35,36 Pharmacogenetic data on ADRsof statin is limited and more research dedicated to this problem isneeded before concrete advises can be given on this notion.

Resistance to antiplateletmedicationBlood platelets maintain appropriate haemostasis upon vascularinjury, but also contribute to the pathophysiology of thrombosis.Thrombosis of atherosclerotic plaques is the most importantunderlying mechanism of CAD and embolic stroke, and conse-quently antiplatelet therapy is the cornerstone of secondary pre-vention in modern CVD treatment.37– 40 Inter-patient variationsin platelet reactivity and responses to antithrombotic treatmentresult in marked differences in the benefits derived from

antiplatelet treatment. Indeed, up to 25% of patients continue toexperience new thrombotic events despite guideline therapy.41,42

The term ‘resistance’ is widely used in such cases, although a clear-cut definition is lacking.43 The current clinical definition regardsresistance as recurrent cardiovascular events despite supposedadequate therapy. Biochemical definitions which are based onresidual platelet activity during treatment measured ex vivo byseveral laboratory tests are however also clinically relevant.Trenk et al.44 for example, found a three-fold increase [95% confi-dence interval (CI) 1.4–6.8, P ¼ 0.004] in the 1-year incidence ofdeath and MI among patients with high residual platelet activityat discharge after percutaneous coronary intervention (PCI)despite clopidogrel. However, although it is likely that biochemi-cally non-responsive patients are also clinically non-responsive,biochemical ‘resistance’ is neither constant in an individual norover time.42 Furthermore, there is an evident lack of concordancebetween laboratory tests used to express resistance.45– 47

Against this background, recent research suggests that geneticvariation makes an important contribution to variation inresponses to the three main groups of anti-platelet therapy:aspirin (see Supplementary material online, Table S2); thienopyri-dine derivates [clopidogrel (see Supplementary material online,Table S3), prasugrel (see Supplementary material online,Table S4), and the P2Y12 receptor antagonist ticagrelor]; and GPIIb/IIIa receptor inhibitors (orbofiban and abciximab) (see Sup-plementary material online, Table S5).

AspirinThe antiplatelet effects of aspirin (acetylsalicylic acid) arise fromirreversible acetylation of cyclooxygenase (COX)-1, which cata-lyses the formation of thromboxane A2, prostaglandin, andrelated metabolites from arachidonic acid.48,49 Blocking COX-1decreases the formation of thromboxane A2, thereby reducingplatelet aggregation.50 Aspirin resistance is poorly defined: apatient can be a non-responder in one test and a normal respon-der in another. Because of this lack of uniformity, the reportedprevalence of aspirin resistance differs widely between studies. Arecent systematic review reported a mean prevalence of aspirinresistance of 24% with a range between 0 and 57%.51

Conflicting results on aspirin efficacyOf the many pharmacogenetic studies on aspirin, Halushka et al.49

were the first to describe an effect of two polymorphisms in theCOX-1 gene, 2842A . G (rs10306114) and 50C . T(rs3842787), that are in complete linkage disequilibrium. Healthyindividuals heterozygous for these polymorphisms showedgreater inhibition of platelet aggregation compared with homozy-gotes of the wild-type allele. Two later studies confirmed thisrelationship in CAD patients.52,53 However, many other studiesfailed to find significant associations between variation of theCOX-1 gene and residual platelet activity54,55 or clinical events,including non-fatal MI or cardiac death.56

Platelet glycoprotein (GP) IIb/IIIa receptors bind fibrinogen,thereby cross-linking platelets and von Willebrand factor(vWF).57 Studies that focused on the 1565T . C polymorphism(rs5918; PlA1/A2) of the GP IIIa (integrin b3) gene producedhighly variable conclusions (see Supplementary material online,

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Table S2). A meta-analysis that included most of these studies con-cluded that the PlA1/A2 variant was significantly associated withaspirin resistance, but only in healthy individuals.45 Co-medicationsused by CVD patients potentially obscured aspirin resistance, whiledifferences in laboratory techniques may have also influencedoutcome.

The meta-analysis also revealed that variations of four othergenes [GP Ia (807C . T, rs1126643), COX-1 (2842A . G/50C. T), P2Y12 (H1/H2, constituted by rs10935838, rs2046934,rs5853517, and rs6809699), and P2Y1 (A1622G, rs701265)] werenot associated with aspirin resistance.45 However, a later relativelylarge study, including 200 high-risk atherosclerosis patients, found astrong association between aspirin resistance and the T allele ofthe 807C . T polymorphism of the GP Ia gene.58 A furtherstudy ruled out any influence of the 2842A . G/50C . T poly-morphism of COX-1 and PlA1/A2 of GP IIIa on platelet responsein a healthy Chinese population, in which these sites were non-polymorphic. However, the study showed attenuated antiplateleteffect during aspirin treatment in the presence of the P2Y1

893CC genotype (rs1065776).55 This last association contrastswith results from 469 Caucasian patients with a history of MI.Here, carriers of the 893T allele had an almost three-fold increasedrisk of aspirin resistance compared with the CC genotype.59

Complications of aspirin therapyA small number of studies focused on genes involved inaspirin-related ADRs. Park et al.60,61 reported that the promoterpolymorphisms 2863C . A (rs1800630) and 21031T . C (rs1799964) of TNF-a and 2509C . T (rs1800469) of TGF-b1 may con-tribute to aspirin-induced urticaria. Piazuelo et al.62 related the car-riage of the A allele of the 27 bp variable number tandem repeats ofeNOS with a decreased risk of upper GI bleeding. Further pharmaco-genetic reports on ADRs of aspirin are necessary given the wide-spread prescription of aspirin.

In conclusion, the precise role of genetic variation in the varia-bility of response to aspirin treatment has yet to be defined. Theonly consistent association is that of the PlA2 variant of the GPIIIa gene and aspirin resistance in healthy individuals. Standardiz-ation of techniques to measure and define response is a prerequi-site for future studies and to establish genetic variation’scontribution to aspirin resistance.

Thienopyridine derivates/P2Y12 receptorinhibitorsClopidogrel resistance is common: the incidence was 21% (95% CI17–25%) in a meta-analysis of patients after PCI.42 Estimates of theincidence vary widely between studies, mainly due to differences inthe time of measurement and dose of clopidogrel. However, thetechnique used to assess clopidogrel responses did not result ina different prevalence of clopidogrel resistance between studies.42

Clopidogrel is an orally administered prodrug. Intestinal absorp-tion is limited by P-GP, an efflux pump encoded by the ABCB1gene. Most of the bioavailable fraction undergoes hydrolysis toan inactive metabolite. Approximately 15% is oxidized by thehepatic cytochrome (CYP) 450 system in two sequential steps togenerate an active metabolite,63 which binds to, and irreversiblyinhibits, the platelet ADP receptor P2Y12. By blocking this

receptor, clopidogrel prevents platelet degranulation and inhibitsconversion of the GP IIb/IIIa receptor to the form that binds fibro-gen and links platelets, thereby inhibiting platelet aggregation.64 –67

Metabolism and resistanceSeveral studies examined the influence of genetic variation in oneor more enzymes of the CYP450 system on clopidogrel resistance.The most consistent finding is that the *2 allele of the CYP2C19gene (rs4244285) (involved in both hepatic oxidative steps) leadsto the formation of an inactive enzyme and, therefore, decreasedplatelet responsiveness to clopidogrel68 (Figure 1). After the firstreport,68 which enrolled healthy male volunteers, studies repli-cated the reduced platelet responsiveness in vitro and establishedan increased risk of cardiovascular events and death during clopi-dogrel treatment in different patient populations (see Supplemen-tary material online, Table S3). Other loss-of-function alleles(*3, rs4986893; *4, rs28399504; and *5, rs56337013) have beenassociated with clopidogrel resistance although not as stronglyand as consistently as the *2 allele, probably reflecting theirlower allele frequencies.69 –72 Furthermore, recent studies associ-ated a gain-of-function allele (*17, rs1248560) and a higher plateletinhibition by clopidogrel and, as a consequence, increased bleedingrisk.73,74

The CYP2C9 loss-of-function allele *3 (rs1057910) has beenassociated with increased residual platelet activity and poorresponder status after a 300 mg clopidogrel loading dosage inhealthy subjects69 and CVD patients.75 Surprisingly, the latterstudy could not detect a similar effect of the risk allele during clo-pidogrel maintenance therapy. The authors hypothesized that sincethis enzyme is involved in the second metabolization step, thereduced enzyme capacity of the *3 allele becomes critical onlywith higher clopidogrel plasma concentrations.63

Studies on genetic variation in other involved CYP450 enzymes,especially CYP3A4 and CYP3A5, did not show a significant influ-ence on platelet responsiveness after clopidogrel treatment (seeSupplementary material online, Table S3). From a clinical point ofview, an important finding came from Gladding et al.,76 whodemonstrated that increasing the clopidogrel dose in patientswith non-responder CYP2C19 polymorphisms can increase theantiplatelet response, indicating that personalizing doses usingpharmacogenetics could potentially optimize treatment.

Drug transport and receptorsAlthough CYP2C19 polymorphisms probably account for most ofthe variability in clopidogrel response, variations in the functionof intestinal efflux transporters might also influence clopidogrelbioavailability. For instance, the 3435C . T SNP of ABCB1(rs1045642) was shown to influence P-glycoprotein transporterexpression, resulting in two- to four-fold lower peak concen-trations of clopidogrel and its active metabolite in TT carriersafter oral administration.77 Two recent studies confirmed thesefindings.70,78 Mega et al.78 also reported that the increased risk ofevents of 3435TT homozygotes increased further in combinationwith a CYP2C19 loss-of-function allele. However, not all publishedpapers show consistent results75 and a recent GWAS could notreproduce the association between this polymorphism and clopi-dogrel pharmacodynamics in healthy volunteers.79


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Another candidate gene encodes the P2Y12 receptor, which isessential for platelet inhibition exerted by clopidogrel, prasugrel,and ticagrelor.80–82 Ziegler et al.83 reported a four-fold increasedrisk for cerebrovascular events in patients who carried the34C . T (rs6809699) variant of the P2Y12 receptor receiving clo-pidogrel for peripheral artery disease. Moreover, Staritz et al.84

associated another polymorphism (52G . T, rs6785930) with clo-pidogrel resistance in patients receiving dual antiplatelet therapy(clopidogrel and aspirin) after PCI. However, other studies couldnot confirm these findings with respect to platelet response orcardiovascular events.70,85,86

Finally, T allele carriers of the GP Ia gene 807C . T (rs1126643)polymorphism show increased platelet aggregation during clopido-grel treatment than non-carriers, increasing their thromboticrisk.87 The same group confirmed these results in patients

receiving dual antiplatelet therapy.88 However, another studycould not confirm these results in 600 acute coronary syndrome(ACS) patients on dual antiplatelet therapy.89 The PlA polymorph-ism of the platelet GP IIIa gene (rs5918) probably does not influ-ence the effect of thienopyridine derivates, although smallstudies report positive as well as negative effects.90,91 Simonet al.70 did not find a significant association of the PlA polymorph-ism in a population consisting of 2208 patients with acute MItreated with clopidogrel and the rate of cardiovascular events(225 deaths and 94 non-fatal MIs or strokes).

In conclusion, resistance to clopidogrel is a major problem, andprediction of the problem could be of great value. The CYP2C19loss-of-function allele *2 shows the most promise in predicting clo-pidogrel resistance and subsequent treatment failure, although thiswas not demonstrated by all studies.92 Many other polymorphisms

Figure 1 Clopidogrel metabolism. From Sangkuhl et al.179 Used with permission of PharmGKB and Stanford University.


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in theoretically promising target genes do not produce consistentresults. Furthermore, proton pump inhibitors, especially omepra-zol, show high affinity for CYP2C19 and might inhibit clopidogrelmetabolism, raising concerns about concomitant use.93 Clinical evi-dence of this adverse drug–drug interaction, however, derivesmainly from observational studies. A recent review concludedthat although definite evidence is lacking and further studies areneeded, clinicians should keep in mind this possibly clinically rel-evant interaction when considering prescribing this combination.93

PrasugrelThe pharmacogenetics of prasugrel, a newer thienopyridine, hasnot been as comprehensively investigated as clopidogrel. Never-theless, several studies indicate that the main contributor to clopi-dogrel resistance, CYP2C19*2, does not affect prasugrel’sefficacy.69,94 In a large study, no significant attenuation of the pra-sugrel response was found in carriers of at least one of the knownloss-of-function alleles of the tested CYP450 genes. Furthermore,in ACS patients, none of the genotypes was associated with clinicalcardiovascular events.94 Prasugrel’s metabolic pathway explainsthis lack of association; CYP2C19 makes only a minor contributionto prasugrel’s metabolism. CYP3A4 and CYP2B6 are largelyresponsible for converting prasugrel to its active form.94,95

CYP3A4 appears not to be very polymorphic and no clear associ-ation emerged between CYP2B6 variants and prasugrel function.94

Prasugrel’s strong antiplatelet effect leads to a highly reducedresidual platelet activity, making any effect of genetic variation dif-ficult to determine. Prasugrel inhibits platelets sufficiently toreduce clinical endpoints despite decreased efficacy arising fromthe polymorphisms.

TicagrelorThe newest P2Y12 receptor antagonist, ticagrelor, appears to besuperior to clopidogrel80,82 and has similar potency as prasugrel.81

A genetic substudy of the largest ticagrelor trial to date, thePLATelet inhibition and patient Outcomes (PLATO) trial, geno-typed 10 285 patients randomized to ticagrelor or clopidogreltreatment. No interaction between ticagrelor and anyloss-of-function CYP2C19 allele (*2 till *8), gain-of-functionCYP2C19*17 allele, or ABCB1 3435C . T genotype emergedwith regard to the either primary efficacy endpoint (compositeof cardiovascular death, MI, or stroke) or any type of major bleed-ing after up to 12 months treatment.74

Glycoprotein IIb/IIIa antagonistsGlycoprotein IIb/IIIa antagonists are mechanistically different fromaspirin, thienopyridine derivates, and other P2Y12 inhibitors. Glyco-protein IIb/IIIa antagonists act primarily outside the platelet bycompetitively inhibiting the receptor essential for platelet bridgingand aggregation.96 Several studies have focused on polymorphismsin the GP IIIa gene and antiplatelet effect, but the results appearinconclusive. One study on orbofiban97 and two on abciximab98,99

found a relationship between the PlA2 allele with reduced plateletinhibition and increased cardiovascular event rate. However, otherstudies did not replicate this association.100 –102 In addition, Shieldset al. developed a model to predict recurrent events during orbo-fiban treatment that included 10 candidate genes: platelet

receptors GP IIIa, PlA1/A2 (rs5918), GP Ia 807C . T(rs1126643), GP Iba, 25C . T (rs2243093); platelet ligandsb-fibrinogen, 2455G . A (rs1800790) and vWF, 21051G . A;interleukins IL-1RN*2, and IL-6, 2174G . C (rs1800795);adhesion proteins E-selectin, 128A . C (rs5361) and P-selectin,715A . C; and metalloproteinase MMP-9, 21562C . T. In 924ACS patients, an association emerged between a combination ofgenetic variants and both recurrent MIs and bleeding outcomesduring orbofiban treatment.103 Since the influence of individualgenetic polymorphisms is usually small, combining multiple variantsin a model might be useful. However, interpreting the results maybe more difficult.

Dosing issues with oralanticoagulantsCoumarin anticoagulants (vitamin K antagonists) are widely used totreat and prevent venous and arterial thrombo-embolisms.However, anticoagulants’ narrow therapeutic range necessitatesfrequent monitoring of the international normalized ratio (INR)coagulation status, which is expensive for health-care systemsand inconvenient for patients. The large individual variability indrug response with all three of the most frequently prescribedanticoagulants (warfarin, acenocoumarol, and phenprocoumon)complicates therapy and makes defining a standard fixed doseunachievable. Besides several patient-related (amongst othersage, weight, body surface area, and diet) and clinical factors(hepatic or renal disease, anaemia, co-medication), pharmacoge-netics explains a large part of the variability in dose require-ments104 – 106 (see Supplementary material online, Table S6).

Increased metabolismFuruya et al.107 first reported the influence of polymorphisms inCYP2C9, the primary enzyme involved in warfarin metabolism,on dose requirement in vivo. Carriers of the *2 allele(rs1799853) required a 20% lower warfarin dose to maintain atarget INR between 2 and 4. Later studies associated the *3(rs1057910) allele with an increased sensitivity to warfarin.108 Invitro, the *2 and *3 genotypes decrease CYP2C9 activity by 30and 80%, respectively.109,110 A large meta-analysis of 39 studiesencompassing 7907 patients111 concluded that compared withthe wild-type CYP2C9*1/*1 genotype, all variant genotypes(*1/*2, *1/*3, *2/*2, *2/*3, and *3/*3) required lower maintenancedoses of warfarin. For instance, maintenance doses in the *2 and *3homozygotes were 36 and 78.1% lower, respectively.

However, using this pharmacogenetic knowledge in clinical prac-tice is difficult. A meta-analysis investigating the safety and efficacyof genotype-guided dosing of warfarin in reducing the occurrenceof major bleeding events and over-anticoagulation found a non-significant trend towards more rapid achievement of a stabledose in the genotype-guided dosing arm.112 Several ongoing ran-domized controlled trials, which are expected to encompassmore than 2500 patients, will help elucidate the role of genetictesting in warfarin management.112


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A second contributorAnother extensively studied gene is that encoding VKORC1(vitamin K epoxide reductase complex subunit 1), which convertsthe oxidized, inactive form of vitamin K to the reduced, activeform. Coumarins inhibit VKORC1, thereby inhibiting activation ofthe vitamin K-dependent clotting factors II, VII, IX, and X.113

A recent meta-analysis analysed the relationship between themean maintenance dose of warfarin and three VKORC1 polymorph-isms (1173T . C, rs9934438; 3730G . A, rs7294; and21639A . G, rs9923231).114 Carriers of 1173T . C and21639A . G needed higher maintenance warfarin doses.

Genetic variation in several other genes—including APOE, gluta-myl carboxylase (GGCX), calumenin (CALU), CYP4F2, epoxidehydrolase 1 (EPHX1), and factor VII (F7)—may also influence war-farin dosage requirements. However, although some studies foundsignificant associations, results were inconsistent.105,115 –119 Finally,recent GWASs identified only CYP2C9 and VKORC1 as major hot-spots, indicating that polymorphisms in other genes probably onlyhave minor influence on warfarin dosing.116,120

Although warfarin is usually the anticoagulant of choice, aceno-coumarol and phenprocoumon are used in most Europeancountries.121 All three drugs are metabolized by CYP2C9.However, phenprocoumon appears to be less influenced byCYP2C9 polymorphisms122 due to significant metabolism by thenon-polymorphic CYP3A4.121 The effect of the VKORC1 poly-morphism is similar for all three drugs.121,123,124

Dosing advice with genetic guidanceIn conclusion, the association between warfarin dose and poly-morphisms of the CYP2C9 and VKORC1 genes seems unquestion-able, as demonstrated by numerous studies and severalmeta-analyses. Polymorphisms in CYP2C9 and VKORC1 togetherwith additional clinical factors including co-medication accountfor 50–60% of the inter-individual warfarin variability.105,125 – 127

Based on this evidence, a free web site is available to help cliniciansestimate the therapeutic dose in patients new to warfarin (http://www.warfarindosing.org) (Figure 2). Furthermore, the US Foodand Drug Administration (FDA) now recommends consideringlower initiation doses of warfarin for patients with certain poly-morphisms in CYP2C9 and VKORC1.128

Suboptimal responses tob-blockersb-Blockers competitively antagonize b-adrenergic receptors(b-AR). Chronic b1-AR activation contributes to the pathogenesisof heart failure and b-AR blockade improves survival, remodelling,and left ventricular ejection fraction (LVEF).129 –131 Other majorindications for b-blocker therapy are hypertension, angina pec-toris, and MI. As with most other drugs, not all patients benefitfrom b-blockers to the same extent, possibly due to genetic vari-ation (see Supplementary material online, Table S7).

Receptors and treatment efficacyThe primary focus of studies examining pharmacogenetic determi-nants of b-blocker response has been the b-AR genes and two

polymorphisms—Ser49Gly (rs1801252) and Arg389Gly (rs1801253)—in the b1-adrenergic receptor (ADRB1) gene in particular.Ser49Gly and Arg389Gly are in linkage disequilibrium and 65% ofthe population carry the Ser49/Arg389 haplotype.132 Not allstudies reported consistent results, but a meta-analysis combiningthree studies (encompassing 504 heart failure patients) concludedthat Arg389 homozygote individuals showed significantly greaterimprovement of LVEF when treated with b-blockers, comparedwith Gly389 carriers.132 Other more recent studies drew thesame conclusion.133,134 However, two large studies reported incon-sistent results on mortality and heart failure-related hospitalization.In the BEST study, the combination of Arg389 homozygote genotypeand bucindolol treatment was associated with decreased mortalityand hospitalization.135 However, no association emerged inMERIT-HT.136 Furthermore, several,137– 139 but not all,140 – 142

studies associated Arg389 homozygotes with an increased effectof b-blockers in decreasing systolic and diastolic blood pressure orheart rate. Furthermore, the Gly allele of Ser49Gly was more com-monly associated with a favourable outcome or improved responseto b-blockers.143 –145 However, many studies did not find anyassociation.142,146,147

Most studies assessing two common polymorphisms in ARDB2(Gly16Arg, rs104213 and Gln27Glu, rs1042714) did not observeany association.146,147 However, two small studies associated theGlu27 allele with increased LVEF after b-blocker treatment com-pared with the Gln27 allele.148,149 A third polymorphism inARDB2, Thr164Ile (rs1800888), occurs in only 1% of Cauca-sians.134,146 Although the Ile164 variant did not have a majorimpact on outcome in a population of 443 heart failure patients,multivariate analysis suggested a possible negative impact ofb-blocker therapy on survival in heterozygous subjects.150

Dosing problems of b-blockersMany b-blockers are metabolized predominately by hepaticCYP2D6,151 which is highly polymorphic with many alleles having adecreased or absent function.152 Several studies report thatCYP2D6 genotype profoundly affects b-blocker concentrations andthe effect seems especially pronounced with metoprolol.153–156

Poor metabolizing genotypes increase metoprolol plasma concen-trations, which results in greater reductions in heart rate and bloodpressure,157–159 and an increased risk of ADRs.159 Although the evi-dence is derived from a few studies, dose adjustments should be con-sidered in patients vulnerable to complications, such as heart failurepatients.160

The use of different b-blockers between, and even within,studies complicates the evaluation of the evidence on the pharma-cogenetics of b-blocker therapy. Differences in receptor specificityof the individual b-blockers could explain this heterogeneity. Forinstance, metoprolol and bisoprolol are b1-AR selective, while car-vedilol and bucindolol are non-selective.161 In summary, the mostconvincing evidence suggests that the variable benefit fromb-blocker treatment is influenced by the Arg389Gly polymorphismof the ADRB1 gene. Furthermore, indisputable evidence shows thatpolymorphisms of the CYP2D6 gene influence b-blocker metab-olism and several reports indicate that poor metabolizers haveincreased efficacy and a greater risk of side effects. The data onother possible related polymorphisms is too thin to draw definite


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conclusions. Combining different risk alleles could provide moreanswers.162

The variable response in patientstaking angiotensin-convertingenzyme-inhibitors

The angiotensin-converting enzyme geneinsertion/deletion polymorphismMost studies examining genetic factors influencing responses toACE-inhibitor treatment evaluated the ACE gene insertion/deletion(I/D) polymorphism (rs4646994) (see Supplementary materialonline, Table S8), which correlates strongly with ACE plasma con-centrations.163,164 Nevertheless, initial results were inconsistent,partly due to limited sample size. Recently, however, the Geneticsof Hypertension-Associated Treatment (GenHAT) study did notfind an association between the I/D ACE polymorphism and the6-year non-fatal cardiac events.165 Similarly, the Perindopril Protec-tion Against Recurrent Stroke Study (PROGRESS) did not find anassociation between this polymorphism and 4-year risk of cardiacevents, mortality, neurological events, or decline or with bloodpressure reduction during perindopril treatment.166 In contrast,in the population-based Rotterdam Study, hypertensive patientson ACE-inhibitors had an increased 10-year mortality risk when

carrying the DD genotype compared with the II genotype, withthe ID genotype in an intermediate position.167 However, the Rot-terdam Study’s observational nature represents a limitation.

In conclusion, although the ACE gene I/D polymorphism was aprime candidate, an association with therapeutic response seemsunlikely. Indeed, since Cambien et al.168 classified this poly-morphism as a potent risk factor for coronary heart disease,many predominantly small positive trials reported similar obser-vations. But a meta-analysis, examining the ACE I/D polymorph-ism with regard to restenosis, showed that small positive studieswere much more likely to be published than negative ones. Thispublication bias distorted the actual association.169

Other targets in therenin–angiotensin–aldosterone systemAngiotensinogen (AGT) is another candidate gene in pharmaco-genetic research on ACE-inhibitors. In another cohort of theRotterdam study, 4097 subjects were analysed for theMet235Thr (rs699) polymorphism of AGT.170 The Thr alleleincreased the risk of MI and stroke in ACE-inhibitor users. Nosignificant association was found with b-blockers. The sameauthors published a paper on a different cohort of 2216 subjectsfrom the Rotterdam study investigating whether the Met235ThrAGT polymorphism modified the risk of atherosclerosis associ-ated with b-blocker or ACE-inhibitor therapy.171 They also

Figure 2 Dosing algorithm warfarin. The flow chart illustrates the publically available warfarin dosing algorithm (http://www.warfarindosing.org). This algorithm incorporates patient factors, clinical parameters, and genetic information to provide an estimation of the loading dose aswell as the maintenance dose of warfarin in patients new to this drug. Clinical testing of the algorithm is currently ongoing (GIFT trial,NCT01006733).�, lower warfarin dose; �, higher warfarin dose. aHigher dose with higher body surface area. bSevere liver disease may pre-dispose to an elevated international normalized ratio. cConcomitant statin use (except pravastatin) decreases warfarin maintenance dose.


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examined the possible relation with the I/D ACE polymorphismand the angiotensin II receptor type 1 (AGTR1) 573C . T(rs5182) polymorphism. None of the candidate polymorphismsstrongly modified the risk of atherosclerosis, measured by arter-ial disease, carotid atherosclerosis, and aortic atherosclerosis inhypertensives taking a b-blocker or ACE-inhibitor.

Furthermore, Su et al.172 genotyped a Chinese population of1447 hypertensive patients from a benazepril trial for several poly-morphisms in AGT, AGTR1, and AGTR2. No association with bloodpressure response emerged for the Met235Thr AGT polymorph-ism. However, subjects with the AA genotype of the rs7079 poly-morphism of the AGT gene showed an enhanced antihypertensiveeffect. Although mortality risk seems to be higher among 235Thrallele carriers of the AGT gene receiving an ACE-inhibitor-basedregimen,170 the risk of atherosclerosis171 or blood pressurereduction172 does not seem to be increased. Further studies exam-ining the influence of this AGT polymorphism might better charac-terize this relationship. Moreover, common haplotypes composedof seven polymorphisms in the AGTR1 gene were also associatedwith a greater antihypertensive effect on ACE-inhibitor therapy.

Prediction of benefitFinally, the first results of the Perindopril Genetic Associationstudy (PERGENE) were recently published.173 PERGENE included8907 subjects and was designed to assess the feasibility of pharma-cogenetic profiling of treatment benefit of ACE-inhibitors inpatients with stable CAD. PERGENE investigated 52 haplotype-tagging polymorphisms in 12 candidate genes within the pharmaco-dynamic pathway of ACE-inhibitors and their relation withcardiovascular mortality, non-fatal MI, and resuscitated cardiacarrest during 4.2 years of follow-up. Two polymorphisms locatedin the AGTR1 gene (rs275651 and rs5182) and one in the bradyki-nin type I receptor (rs12050217) gene were significantly associatedwith perindopril’s treatment benefit. Combining these three poly-morphisms in a pharmacogenetic score identified patients who didnot benefit from perindopril (26.5%) (Figure 3). The event rateincreased significantly in these patients allocated to perindopril(6.3–10.4%, Pinteraction , 0.0001). The authors replicated this phar-macogenetic score in a subgroup of the PROGRESS trial.173 Fivepolymorphisms of the ACE gene (one in complete linkage disequi-librium with the I/D polymorphism) were shown not to be

Figure 3 Pharmacogenetic score proposed by the PERGENE study for prediction outcome of treatment with angiotensin-convertingenzyme-inhibitors. Results of the PERGENE study indicated that carriage of three or more minor alleles (risk alleles) of rs275651 A . T,rs5182 C . T, and rs12050217 A . G corresponded with an increased risk of cardiovascular mortality, myocardial infarction, or resuscitatedcardiac arrest during treatment with perindopril compared with placebo. Clinical consequences of these findings, whether indeed patients withthis specific risk profile should not receive angiotensin-converting enzyme-inhibitor treatment, remain to be prospectively studied. Modifiedfrom Brugts et al.173


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associated with the endpoints, again stressing that the ACE I/D genevariation does not seems to carry clinical value. The PERGENE trialtakes an important step closer to realizing individualized therapyfor ACE-inhibitors, but requires replication.

Angiotensin receptor blockers (ARB) inhibit therenin–angiotensin–aldosterone system through a different mech-anism than ACE-inhibitors. Although some small studies investi-gated pharmacogenetics of ARBs, replication in largerpopulations is necessary before drawing conclusions (see Sup-plementary material online, Table S8).

Future perspectives andconclusionDuring the Colloquium, mentioned in the introduction, all abovediscussed subjects were covered and the following conclusionswere made. Elucidating genetic variation in patients with CVDmay enable tailored therapy, thereby optimizing efficacy whileminimizing costs and adverse effects. Nevertheless, despite thevast amount of available publications, pharmacogenetics of CVDis not yet established in clinical practice. Indeed, studies of mostpolymorphisms produced inconsistent results due to thecomplex systems underlying CVD, which means variation in asingle gene usually produces only a small effect on clinical pheno-types. Very large patient cohorts are needed to convincingly detectthese subtle differences. Large studies designed to detect pharma-cogenetic association (e.g. large GWAS) are ongoing and will prob-ably be of great value in unravelling the current inconsistencies aswell as elucidating associations of genetic variation in other targetgenes. Moreover, new approaches like sequencing might result innew targets for subsequent research.

The relevance and usefulness of GWAS have recently beenreviewed by Daly174 (Table 2) and commercially available arrays,like the Drug Metabolizing Enzymes and Transporters (DMET)

platform, offer systematic exploration of potentially relevant path-ways.175 However, pharmacogenetics needs evidence other thanGWAS to convince cardiologists of its clinical utility. In particular,large prospective studies should investigate the effect of genetictesting on clinical outcomes and stratify patients to determinegroups for which genetic testing is relevant. For example, theJUPITER trial showed that statin treatment is more beneficial insubjects with high C-reactive protein levels.176 Development ofrisk models combining clinical characteristics (age, gender, andhistory), patient characteristics (for instance blood pressure,weight, and echocardiographic parameters), biomarkers, and gen-etics will be most useful and informative.

Besides the genetic variation depicted in Table 3, the evidence formost other pharmacogenetic associations is not strong enough forclinical application. Nevertheless, currently several guidelines ondrug prescription already contain pharmacogenetic information.Very recently, Swen et al.177 published an update of the currentDutch guidelines implementing pharmacogenetics in several thera-peutic recommendations. Also, over 60 FDA-approved drug labelscontain pharmacogenetic information.178 For instance, in 2007, theFDA recommended initiation warfarin doses for carriers of certainCYP2C9 and VKORC1 polymorphisms. Moreover, in 2009, the FDAadded a warning to the clopidogrel prescribing information to high-light the impact of the poor metabolizer genotypes of CYP2C19.Finally, the pharmacogenetic score developed in the PERGENEtrial seems to be able to identify patients who will not benefit fromACE-inhibitor treatment and the clinical consequences of thisknowledge, whether indeed patients with this specific risk profileshould not receive ACE-inhibitor treatment, should be prospectivelytested.

Ongoing large clinical trials, primarily designed as pharmacoge-netic studies, and GWAS with large study populations promiseto provide more convincing evidence. Overall, there are enoughreasons to remain optimistic that, even though we are taking

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Table 2 GWAS on pharmacogenetics of cardiovascular drugs

Study name Drug Outcome measure Population size (disc./repl.)

LowestP-value

Associated gene(s) Ref.

TNT Atorvastatin Lipid-loweringresponse

1984/3761 5.5E230 APOE, PCSK9, HMGCR 17

TNT, CAP, andPRINCE

Statin Lipid-loweringresponse

3936a 1.9E208 CLMN, APOC1 19

SEARCH and HPS Simvastatin Myopathy 85|90b/21|16 643b 4.0E209 SLCO1B1 32

PAPI Clopidogrel Platelet aggregation 429/227 1.5E213 CYP2C19 79

— Warfarin Maintenance dose 181/374 2.6E213 VKORC1, CYP2C9 120

WARG Warfarin Maintenance dose 1053/588 5.4E278 VKORC1, CYP2C9,CYP4F2

116

Rotterdam Study Acenocoumarol Maintenance dose 1451/287 2.0E2123 STX4A (VKORC1),CYP2C9

124

TNT, Treating to New Targets study; CAP, Cholesterol And Pharmacogenetics study; PRINCE, PRavastatin/Inflammation CRP Evaluation study; SEARCH, Study of theEffectiveness of Additional Reductions in Cholesterol and Homocysteine; HPS, Heart Protection Study; PAPI, the Amish Pharmacogenomics of Anti-Platelet Intervention study;WARG, WARfarin Genetics study; disc., discovery cohort; repl., replication cohort.aCombined number of patients included in the meta-analysis.bCase|control.


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small steps at a time, we are heading to an era where we can finallyuse pharmacogenetics in clinical practice to optimize treatment forthe individual patient.

Supplementary materialSupplementary material is available at European Heart Journalonline.

AcknowledgmentsOur thanks goes out to the speakers during the ‘Pharmacogeneticsof cardiovascular drugs Academy Colloquium’ of the RoyalNetherlands Academy of Arts and Sciences for their contributionto the symposium: A. Isaacs, Professor A. Uitterlinden, ProfessorA. Zwinderman, Professor M.L. Simoons, Professor H.-J.Guchelaar, B.R. Winkelmann, A. Briggs, R. van Schaik,M. Ingelman-Sundberg, Professor J.W. Jukema, A.-H. Maitland v/d.Zee, Professor Schaefer, D. Voora, G. Rudez, J. Oldenburg,P. Sharma, G. Pare, P. v/d. Harst, J.J. Brugts, Professor W. vanGilst, C.R. Bezzina, and Professor J. Danser.

FundingThe research leading to these results has received funding from theEuropean Union’s Seventh Framework Programme (FP7/2007-2013)under grant agreement (no. HEALTH-F2-2009-223004). Supportedby grants from the Interuniversity Cardiology Institute of theNetherlands (ICIN) and the Durrer Center for CardiogeneticResearch both Institutes of the Netherlands Royal Academy of Artsand Sciences (KNAW), the Netherlands Heart Foundation, theCenter for Medical Systems Biology (CMSB), a centre of excellenceapproved by the Netherlands Genomics Initiative/Netherlands Organ-ization for Scientific Research (NWO), and the Netherlands Consor-tium for Healthy Ageing (NCHA). J.W. Jukema is an established clinicalinvestigator of the Netherlands Heart Foundation (2001D032). Thefunders had no role in study design, data collection and analysis,decision to publish or the preparation of the manuscript.

Conflict of interest: none declared.

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Table 3 Best explored single nucleotidepolymorphisms in the field of cardiovascularpharmacogenetics

Gene SNP Drug Effect ofvariant

CYP2C19 *2 (rs4244285) Clopidogrel Decreasedeffect

CYP2C9 *2 (rs1799853) Warfarin Increasedeffect*3 (rs1057910)

VKORC1 21639A . G(rs9923231)

Warfarin Decreasedeffect

1173T . C(rs9934438)

ACE I/D (rs4646994) ACE-inhibitors No effect


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A systematic review on pharmacogenetics in cardiovascular disease