With the understanding of interindividual differences at the level of DNA sequence, the ability to relate drug effects to gene variants (pharmacogenes) has been enhanced. The consequences of genetic variations range from inefficiencies to adverse drug reactions (ADRs). The variations in the ADME genes that modulate drug absorption, distribution, metabolism and excretion are significant. The genetic variability may contribute with a proportion of 25-40% in the overall unexpected drug response. Therefore, it is important in assessing the variability of pharmacotherapy include other primarily clinical and environmental factors like comorbidities and polytherapy with an increased risk of interactions and therefore ADRs. Correlations of single gene and drug have been confirmed for some cardiovascular (CV) drugs, however, there are a significant number of those drugs for which we do not have unambiguous pharmacogenomics data that could be translated into clinical guidelines. This applies primarily to direct oral anticoagulants, ticagrelor, prasugrel, rosuvastatin, fluvastatin, most antihypertensives and antiarrhythmic agents. CV patients are often on polytherapy, and older patients also have other comorbidities that increase the risk of drug interactions. Establishing a multidisciplinary research group (clinical specialists, pharmacist and laboratory analysts) creates the precondition for systematic investigation of the ADRs of CV drugs. The case study of patients with adverse reactions and control subjects will include 800 subjects on CV polytherapy with medicines primarily those for which reliable pharmacogenetic data are missing. In a multivariate statistical analysis of the assessment of ADRs, besides gene variants, other non-genetic, clinical factors will be included. The results of the project will result in new insights into the multiple interactions of cardiovascular drugs and related genes with high applicability potential in clinical practice.