**5. Statins**

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have reduced coronary and cerebrovascular events and overall mortality when used for both primary and secon‐ dary prevention of ischemic heart disease [105]. Several known gene polymorphisms are as‐ sociated with the treatment progress [106, 107].

Some studies examined polymorphism in the gene encoding cholesteryl ester transfer pro‐ tein (CETP), which is involved in the metabolism of high-density lipoprotein (HDL). Pravas‐ tatin-treated patients with either the B1/B1 or B1/B2 genotype (B1 presence and B2 absence of polymorphism) had significantly less atherosclerotic progression than patients receiving a placebo. Placebo-treated patients with the B2/B2 genotype had the least progression. How‐ ever, pravastatin-treated patients with the B2/B2 genotype (16% of the study population) de‐ rived no benefit from pravastatin [108, 109].

The substitution (-455G/A) of the fibrinogen gene was found to be associated with an in‐ creased risk of myocardial infarction and stroke. During follow-up, placebo-treated pa‐ tients homozygous for the -455A genotype had the greatest disease progression; although, no association was found with benefit in disease progression in patients on pravastatin therapy [110].

A five year study of pravastatin therapy in patients with a history of myocardial infarction and hypercholesterolemia showed that the largest benefit of pravastatin treatment in reduc‐ ing these events occurred in patients with the platelet GP IIIa PlA1/A2 genotype who also carried at least one D allele of the ACE gene [111, 112].

An effect of polymorphism in the alloprotein gene was found on simvastatin therapy in a Scandinavian study. Among patients who received the placebo and had at least one apolipo‐

protein e4 allele, the relative risk of death from all causes was higher than in simastatin pa‐ tients with the same polymorphism [113]. This study demonstrates the potential clinical value of the alloprotein APOE genotype as a robust marker for low-density lipoprotein (LDL) responses to statin drugs, which might contribute to the identification of a particular‐ ly drug-resistant subgroup of patients [114].

**6. Antiarrhythmic**

syndromes [126].

the general population [133-135].

**7. Antiplatelet agents**

**7.1. Aspirin**

Many antiarrhythmic agents have antagonistic effects on sodium ion and potassium ion channels in the heart. A risk of proarrhythmic effects of antiarrhythmic drugs and its mechanism is associated with genetic variations. Some evidence indicates that polymor‐ phisms in genes encoding components of cardiac ion channels have been associated with congenital arrhythmia syndromes, such as long-QT and idiopathic ventricular fibrillation

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The fact that the risk of drug-induced arrhythmia usually increases with increasing drug concentrations also indicates the involvement of liver enzyme polymorphisms. The CYP2D6 gene regulates cytochrome P450 metabolic pathways and some evidence shows an associa‐

A number of polymorphisms in the N-acetyltransferace 2 gene contribute to different acety‐ lator phenotypes. Rapid acetylators have increased conversion of procainamide by N-acetyl‐ transferase 2 to N-acetylprocainamide (NAPA) consequently leading to the QT-interval prolongation, and life-threatening ventricular arrhythmias. Slow acetylators will attain an increased concentration of procainamide levels with normal procainamide dosages, which

Sotalol, dofetilide and quinidine increase the chances of QT interval prolongation, polymor‐ phic ventricular tachycardia and torsades de pointes. Several genes encoding ion channels or function-modifying subunits were associated with these syndromes [129],[130-132].

One study suggested that a NOS1AP variant in the gene encoding an accessory protein for neuronal nitric oxide synthase, was associated with total and cardiovascular mortality dur‐ ing treatment with dihydropyridine calcium channel blockers. Variants in NOS1AP also have been reported to modulate the risk of arrhythmias, at equivalent QT interval durations, in patients with the congenital long QT syndrome and to modulate risk for sudden death in

Pharmacogenetic studies of aspirin response to date have found associations with a few genes. It was reported that PLA2 (Leu59Pro) carriers, the variant in platelet glycoprotein IIIa, have impaired aspirin responses. After seven days of aspirin therapy in healthy volun‐ teers, plasma prothrombin fragment concentrations in bleeding-time wounds were reduced in 23 of 25 PLA1 homozygotes, compared with 9 of 15 PLA2 carriers [136]. A meta-analysis [137] of 50 polymorphisms in 11 genes reported in 31 studies with a combined sample size of 2834 subjects suggested that the common PLA1/2 polymorphism does confer aspirin re‐ sistance (odds ratio in healthy subjects=2.36; P=0.009); however, when combining both

tion between poor metaboliser phenotype and antiarrhythmic drug toxicity {127}.

can lead to a procainamide- induced lupus-like syndrome [128].

Genetic variants in CYP3A4, which metabolises simvastatin, atorvastatin and lovastatin, have been associated with variability in statin efficacy. Both a nonsynonymous polymor‐ phism (M445T) as well the CYP3A4\*4 haplotype have been associated with lower LDL cho‐ lesterol levels with atorvastatin. However, in carriers of either a CYP3A4 promoter polymorphism (A290G) or the CYP3A4\*1G haplotype the lipid-lowering effect of statins is not demonstrated [115-117].

Variation in Hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and low-density lip‐ oprotein receptor (LDLR) genes are associated with the LDL-lowering effect of statins. The H7 haplotype within HMGCR, defined by the presence of three intronic SNPs, has been as‐ sociated with an 11% to 19% reduction in LDL cholesterol with statin treatment in multiple independent populations as well as ethnically diverse population-based cohorts [107, 114, 118]. The H7 haplotype has been shown to interact with other genetic variants, including a second HMGCR haplotype, H2, as well as the LDLR L5 haplotype, defined by six SNPs within the LDLR 3′ untranslated region. Ethnic variations in LDL cholesterol-lowering with statin treatment is also demonstrated in African-Americans who carry multiple copies of these haplotypes versus any haplotype alone [106, 118, 119].

Statin-related myotoxicity, especially rhabdomyolysis, is the subject of medical concerns as it requires changes in medications and treatment discontinuation. It was found that variants in CYP3A5 and solute carrier organic anion transporter family (SLCO1B1) gene can be po‐ tential predictors of myotoxicity [120-123].

Increased risk of coronary artery disease, coronary heart disease and myocardial infarction are associated in some studies with a missense SNP, Trp719Arg, in the KIF6 gene (kinesin family member 6). Statin treatment significantly reduce coronary events in carriers of Trp719Arg, and SNPs in high linkage disequilibrium with it, whereas no benefit of statin treatment is reported in noncarriers [124].

The differences in drug-drug interaction profiles among available statins offer the possibility of reducing the risk of myotoxicity among high-risk patients. The risk of developing the rhabdomyolysis condition with statin therapy increases at higher therapeutic doses. This ef‐ fect is increased by combination with certain other medications due to drug-drug interac‐ tions. Co-administration of drugs that inhibit the cytochrome P450 (CYP) enzymes responsible for metabolizing statins, or that interact with the organic anion-transporting pol‐ ypeptides (OATPs) responsible for statin uptake into hepatocytes, substantially increases the risk of developing myotoxicity. Pitavastatin, a novel statin approved for the treatment of hy‐ percholesterolemia and combined (mixed) dyslipidemia, is not catabolized by CYP3A4, un‐ like other lipophilic statins, and may be less dependent on the OATP1B1 transporter for its uptake into hepatocytes before clearance [125].
