P1619Polymorphic variants rs6684209 and rs7521023 of the calsequestrin 2 gene as risk factors for adverse course of heart failure

Abstract

Abstract Calsequestrin 2 protein binds most of Ca2+ ions inside the sarcoplasmic reticulum and is involved in the regulation of Ca2+ release through the ryanodine receptors of the cardiomyocytes. Due to mutations in the CASQ2 gene, there is an enhanced release of ions from the sarcoplasmic reticulum, which leads to disruption of Ca2+ homeostasis. In turn, this is a risk factor for the development and progression of chronic heart failure (CHF) and heart rhythm disturbances. Purpose Investigate the association between polymorphic variants rs6684209, rs7521023 of the CASQ2 gene and heart failure in patients with coronary artery disease (CAD). Methods The sample included 174 patients with CAD complicated by CHF. Of these, 115 (66.1%) are men and 59 (33.9%) are women aged 64 (59; 70) years. The functional class (FC) of CHF was defined according to the classification of the New York Heart Association (NYHA). The distribution of CHF FC I, FC II, FC III was 25 (14.4%), 97 (55.7%), 52 (29.9%). The left ventricular ejection fraction in the patient sample was 62% (52; 66). The polymorphic variants rs6684209 (115707991C>T in the intron) and rs7521023 (115700759G>A in 3-UTR) of the CASQ2 gene were determined by real-time polymerase chain reaction. For the analysis of the qualitative data, Pearson's χ2 test or the Fisher two-sided exact test was used. Results In the total sample of patients, there was no assotiation between the rs6684209 variant of the CASQ2 gene and the clinical picture of CHF. However, among men, but not women, differences in the frequency of FC I, II, III CHF (p=0.029) between CC, CT and TT genotypes were found. In addition, among carriers of the CT genotype, diastolic myocardial dysfunction occurred in 80% of patients, while among CC homozygotes, its frequency was 63.1% and was not observed in TT homozygotes (p=0.034). At the same time, there were more patients with heart rhythm disorders among CC homozygotes than among carriers of the T allele (60.8% vs. 45.2% for CT and 0% for TT, p=0.046). The association of the polymorphic variant rs7521023 with the course of CHF was assessed. A significant (p=0.044) increase in the frequency of left atrial enlargement in GG homozygotes (69.2%) compared with carriers of the AA (45.1%) and AG (41.9%) genotypes was found in the total sample of patients. Gender features were absent in the association of variant rs7521023 with risk factors for the development and progression of CHF. Conclusion The polymorphic variants rs6684209 and rs7521023 of the CASQ2 gene are associated with the severity of CHF and the risk of developing heart rhythm disturbances. With the CT genotype of the rs6684209 variant, diastolic myocardial dysfunction was more common, but the T allele appeared to be protective against the development of heart rhythm disturbances. Carrier genotype GG (rs7521023) is a risk factor for dilatation of the left atrium, which in turn can serve as a substrate for the development of arrhythmias. Acknowledgement/Funding This work was supported in part by the Russian Foundation for Basic Research, No. 17-04-01450 A.