**2.1. β-blockers**

β-blockers through binding to β-adrenergic receptors (BAR) antagonise the binding of en‐ dogenous agonists. Variations in the gene encoding the β1-adrenergic receptor probably in‐ fluence the treatment outcome. Two single nucleotide polymorphism (SNPs), resulting in Ser49Gly and Arg389Gly were identified and these variants demonstrate altered biological function in vitro, including enhanced agonist induced adenylyl cyclase activation by Gly49 compared to Ser49 and by Arg389 compared to Gly389 [11].

Some studies have shown that the Arg389Arg genotype and Ser49/Arg389 haplotype are as‐ sociated with a greater response to blood pressure-lowering metoprolol [12].

The differential survival of Acute Coronary Syndrome (ACS) patients treated with βblockers was associated with patients' β-adrenergic receptors 2 variant Gly16Arg and Gln27Glu genotypes; however, β-adrenergic receptors 1 variants showed no significant as‐ sociations [13, 14].

No significant correlation has been found for outcomes of death, MI or stroke in coronary artery disease patients on atenolol treatment and β-adrenergic receptors variants or haplo‐ types [15] and β-adrenergic receptors 2 variants in MI and stroke outcomes. However, the case-control study found significant interaction with two SNPs in β-adrenergic receptors variant and cardiovascular complications [16, 17].

Angiotensin-converting enzyme (ACE) genes variations were also associated with β-block‐ ers therapy outcome. In heart failure, patients survival without a transplant, has been as‐ sociated with the angiotensin-converting enzyme I/D genotype (insertion/deletion). Patients with the D allele may derive greater benefits from pharmacologic interventions with Beta-blocker treatment, probably through the decrease of sympathetic nervous sys‐ tem activity [18].

The effects of the CYP450 enzyme systems has been studied intensively during the last years and its role in the metabolism of drugs and other endogenous and exogenous chemicals is well defined. Numerous publications confirm the association of these enzymes with drugdrug, drug-toxins and drug-food interactions. Polymorphisms in the gene coding for the CYP2D6 isoenzyme, which catalyses the metabolism of β-blockers such as metoprolol, car‐ vedilol, timolol, and propranolol, may also affect blocker response. It has been demonstrat‐ ed that the clearance of the R(+) enantiomer of carvedilol was 66% lower and the area under the concentration-versus-time curve 156% higher among poor metabolizers than extensive metabolizers [19-22].

Some studies showed association with other genes. Genes involved in calcium signalling - CACNA1C, CACNB2, and KCNMB1- were found to be associated with myocardial infarc‐ tion or stroke with β-blockers versus calcium channel blockers [23-25]. Variable stroke risk by genotype was described for an MMP3 promoter polymorphism in patients treated with lisinopril [26] and different treatment-related outcomes with thiazides and β-blockers, but not diltiazem, by NEDD4L (protein reduce renal tubular expression of epithelial Na+ chan‐ nel) genotype [27].

Finally, the two studies by Schelleman et al reported no β-blocker interactions (for outcomes MI or stroke) variants of angiotensin receptor II type 1 (AGTR1) and ACE [28, 29].
