# Factors Determining Ticagrelor-Induced Dyspnea in Patients with Acute Coronary Syndrome
## 4 Discussion
Up to date, there are no significant results of clinical trials that could prove the impact of _CYP2C19_, _ABCB1_, or other gene polymorphisms on the pharmacodynamic parameters of ticagrelor [10]. The results of this study show that the _FBG-C148T_ gene polymorphism was associated with dyspnea. However, multiple logistic regression analysis did not confirm the impact of this variant on the development of dyspnea in the total sample of patients. The synthesis of fibrinogen is regulated by the \(\beta\)-fibrinogen promoter. The -C148T allele is associated with higher levels of inflammatory markers. It is located close to the interleukin-6-response element controlling fibrinogen gene expression during the acute phase of inflammation. Thus, according to [PERSON] et al., the _FBG-C148T_ gene polymorphism is associated with the inflammatory response to advanced atherosclerotic lesion (two- and three-vessel disease) [39]. Inflammation is one of the most important components of atherosclerotic artery lesion. The more advanced the atherosclerotic lesion, the greater the inflammatory response observed [40]. In the presence of multiple atherosclerotic coronary lesions, patients usually experience the symptoms of angina pectoris, directly related to the extent of atherosclerotic disease, with dyspnea being one of the typical clinical symptoms [41]. In our study, we showed that lower platelet activity might be related to the sensation of dyspnea. Platelet activity may also show the activity of the inflammatory system [42]. Thus, it is probable that the lower rate of sensation of dyspnea is related to the lower concentration and clinical effect of ticagrelor in patients having _FBG_ variants. Many clinical trials have proved the impact of the _CYP2C19_ polymorphism on predicting the clinical outcomes of patients with ACS who underwent PTCA and stenting and received treatment with a combination of clopidogrel and aspirin. It is known that ticagrelor does not require the activation of the enzyme coded by the _CYP2C19_ gene [10]. Some studies have searched for possible associations between the effect of ticagrelor and the _CYP2C19_ polymorphism, but the data reported are controversial. The study by [PERSON] et al. suggested that the _CYP2C19_ polymorphism could be related to an increased risk of bleeding in Asian patients who received treatment with ticagrelor [43]. [PERSON] reported that _CYP2C19_ appeared to have no impact on the pharmacodynamic characteristics of ticagrelor [10]. The pooled analysis of the RESPOND and ONSET/OFFSET clinical trials also showed that the antiplatelet activity of ticagrelor was not related to the _CYP2C19_ genotype [10; 44]. However, there are contradictory data indicating that the _CYP2C19_ genetic polymorphism is responsible for the pharmacokinetics of ticagrelor. The _CYP2C19_ *1*1 variant was found to be associated with lower platelet aggregation in ticagrelor users [19; 45]. The results of our study did not confirm an association between the occurrence of dyspnea and the _CYP2C19_ variants. Previous research has found that the _CYP4F2_ gene polymorphism has an impact on the effectiveness of treatment with ticagrelor. The _CYP4F2_ (rs3093135) T allele was associated with a greater incidence of bleeding events during therapy with ticagrelor [19]. The TT genetic variant was more common among those patients who reported bleeding events within a 3-month period after hospitalization [19]. [PERSON] et al. observed that the _CYP4F2_ gene polymorphism had a remarkable effect on the pharmacokinetic parameters of ticagrelor [18]. The findings of our study did not show any association between the occurrence of dyspnea and _CYP4F2_ variants. Based on the accumulated body of knowledge, we made an assumption that the occurrence of dyspnea might be related to high ticagrelor plasma levels, tightly related to platelet aggregation and atorvastatin use [26; 27]. Large randomized well-controlled studies are required to identify the impact of clinical and genetic factors involved in dyspnea occurrence. [PERSON] et al.