Search

Purpose Heart failure is one of the main problem in the health care system. The best option of the treatment is heart transplantation (HT). Left ventricular assist device (LVAD) implantation is the best option of alternative treatment instead of HT. Outcome of the LVAD treatment is usually followed with side effects of bleeding and thrombosis. To reduce side effects patients are prescribed with antithrombotic therapy warfarin, which can be followed with side effects because of incorrect individual dosage. Warfarin dosage can be identified according to the results of genetic polymorphisms CYP2C9 and VKORC1. The study is aimed to identify genetic associations of SNP polymorphisms rs1799853, 1057910, rs9923231. Methods Venous blood samples were recruited from 98 patients with implanted LVAD at the National Research Center for Cardiac Surgery. Heart failure patients contained 92 males and 6 females (52.7±10.95 years old) with implanted LVAD devices. The control group contains ninety-five (n=95) conditionally healthy individuals. Warfarin treatment was prescribed after LVAD implantation monthly (after 1st month, 3rd, 6th, 9th and after 1 year etc). SNP polymorphisms were genotyped in case and control groups by real-time polymerase chain reaction with TaqMan probes. Results Genotyping test results were not statistically significant. Case and control groups did not have mutant type of genotypes TT (rs1799853) and CC (rs1057910). Genotype frequency of CC genotype rs1799853 was slightly higher in the case group (92.9% vs.92.6%, p = 1.000). The second SNP rs1057910 had higher frequency of AA genotypes in case group (92.9% vs. 86.3%, p = 0.161). Mutant genotype TT of rs9923231 was slightly higher in the control group (37.9% vs.36.7%, p = 0.718). Monthly clinical dosage of warfarin was compared between three genotypes of rs9923231. Warfarin dosage was significantly associated between three genotypes (p Conclusion Research need to include other polymorphisms for deeper research about individual warfarin dosage and their associations with side effects.

Purpose Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with considerable morbidity and mortality. Multiple genes and genetic loci affecting AF susceptibility have been identified using positional cloning and candidate gene approaches The extent to which such polymorphisms contribute to AF is unknown. The aim of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a cohort of unrelated AF patients from Kazakhstan. Methods We sequenced 96 candidate genes in 102 Kazakhstani patients with AF using customized targeted gene panel (Haloplex, Agilent Technologies). Variants detected were compared with variants observed in the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency 0.04%) AAC variants. ACMG/AMP guidelines were applied for variant interpretation of clinical significance - pathogenic (P), possibly pathogenic (PP), variant of uncertain significance (VUS), possibly benign (PB), benign (B). The ClinVar, Varsome and HGMD databases were also used. Results Median age at AF onset was 47.0 years, and 31.3% had a family history of AF. Totally 456 variants were identified in 74 genes for the overall study group. Variants included one in/del variant, four splice-site variants and 451 single-nucleotide variants (SNV) within the coding exonic regions. 168 HGMD mutations (61 unique) were observed in 37 genes. Classification of 456 variants according to ACMG guidelines showed that 13(2.9%) variants were classified as pathogenic, 13(2.9%) - likely pathogenic, 145 (31.9%) - uncertain significance, 109 (23.8%) likely benign and 175 (38.4%) benign. 31 rare AAC variants were identified in 20 of 102 AF patients. Among them three pathogenic variants KCNQ1 c.477+1G>A, KCNJ2 R218Q and KCNE2 T10K C29A (PP) were identified. Conclusion Our study shows that individuals presenting with AF carry rare mutations and potentially pathogenetic sequence variants in classical cardiac risk genes in almost 20%. No very rare AAC variants were identified in 80% of AF patients. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors.

Purpose Ventricular fibrillation (VF) and ventricular tachycardia (VT) are major causes of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (iVT). Recent achievements in molecular genetics has unveiled the complex molecular basis of many cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. We aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias using targeted next-generation sequencing (NGS) approach in Kazakhstani patients with arrhythmias. Methods The study included 92 Kazakhstani patients (mean age of 31.2 years at the time of the VT event), diagnosed with iVT, VT and coronary heart disease (CHD), VT and dilated cardiomyopathy (DCM). We developed a targeted panel of 96 known cardiac disease genes, associated with cardiomyopathy and arrhythmia. Results We observed 168 mutations (61 distinct) listed in the Human Genome Mutation Database and another 256 rare/unique variants with elevated pathogenic potential. Also we analyzed observed mutations according to ACMG guidelines. The majority of VT/CHD patients carried known mutations and rare variants with high pathogenetic potential in the same genes and at a comparable frequency as observed for VT/DCM and iVT patients. The most abundant mutations observed for the CHD group locate to MYBPC3, DMD, LAMA2, MYH6 and GAA. A subset of patients originally diagnosed with iVT carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Conclusion Our study indicates that individuals presenting with VT either secondary to CHD, DCM or of idiopathic etiology carry multiple rare mutations and potentially pathogenic sequence variants in classical cardiac risk genes in a similar pattern and at a comparable frequency. Molecular genetic testing of patients with life-threatening ventricular arrhythmia with NGS identifies a molecular-genetic cause in a significant proportion of patients.

Purpose Chronic heart failure (CHF) is one of the most severe and adverse diseases of the cardiovascular system, which requires heart transplantation (HT) for patient. Implantation of the left ventricular assist device (LVAD) is the treatment option instead of HT. LVAD can be implanted as a bridge to transplantation and destination therapy (DT). Unfortunately, DT of the LVAD has side effects such as bleeding and thrombosis. These side effects occur because of the non-physiological high shear stress of the LVAD, which causes platelet degradation. However, side effects might occur because of the genetic polymorphisms in coagulation factors, platelet receptors etc. The purpose of the study is to identify the influence of the coagulation factor F5, F7 and FGB polymorphisms in LVAD patients. Methods Venous blood samples were recruited from 100 patients with implanted LVAD at the National Research Center for Cardiac Surgery. Patients were prescribed with the dose of the warfarin according to the clinical protocol. Patients were divided into two groups: 1.Case study - patients with side effects; 2. Control study - patients without side effects. Genomic DNA was extracted by using the PureLink™ Genomic DNA Mini Kit (Invitrogen, UK). Genotyping of polymorphisms F5 (rs6025), F7 (rs6046) and FGB (rs1800790) was done by real-time polymerase chain reaction with TaqMan probes. Results Genotyping results of Factor Leiden V (F5) showed that most of the patients (99%) has wild type of genotype (C/C) which has no risk to thrombosis. On other hand, genotyping results of F7 and fibrinogen beta (FGB) polymorphisms presented different percentage results from F5. Results of polymorphism F7 showed wild type of genotype G/G in 76% patients, whereas only 3% patients has mutant genotype A/A which has no risk to thrombosis. Mutant genotype A/A of FGB polymorphism was expressed only in 3% of patients, which has high risk to thrombosis. Mutant version of polymorphisms shows that some LVAD patients have high risk to side effects apart from high shear stress. Conclusion The study has presented that side effects might happen because of the individual genome differences in LVAD patients. Some patients demonstrated high risk of side effects on destination therapy as well as according to genotyping results too.

Channelopathies, caused by disturbed potassium or calcium ion management in cardiac myocytes are a major cause of heart failure and sudden cardiac death worldwide. The human ryanodine receptor 2 (RYR2) is one of the key players tightly regulating calcium efflux from the sarcoplasmic reticulum to the cytosol and found frequently mutated (T; p.D4631V) in a CPVT patient and a novel rare variant (c5428G>C; p.V1810L) of uncertain significance in a patient with VT of idiopathic origin which we suggest represents a low-penetrance or susceptibility variant. In addition we identified a known variant previously associated with arrhythmogenic right ventricular dysplasia type2 (ARVD2). Combining sets of prediction scores and reference databases appeared fundamental to predict the pathogenic potential of novel and rare missense variants in populations where genotype data are rare.