Background. The development of myelofibrosis (MF) is driven by complex molecular genetic events that include driver somatic mutations responsible for the constitutive activation of the JAK/STAT signaling pathway (JAK2, CALR, and MPL), additional mutations affecting epigenetic regulators (TET2, ASXL1, IDH1/2, etc.) and RNA splicing (SRSF2, U2AF1, SF3B1, etc.), as well as genetic aberrations that contribute to genomic instability and disease progression.Aim. To analyze driver (JAK2, CALR, MPL) and prognostic (ASXL1) somatic mutations in patients with MF and evaluate their impact on survival.Materials and methods. The study included 29 patients diagnosed with MF, selected by hematologists from the City Clinical Hospital No. 7 and Regional Clinical Hospital (Krasnoyarsk).Results. 26 (89.6 %) out of 29 examined patients had some driver mutations in JAK2, CALR, MPL genes. The p.V617F mutation in the JAK2 gene was found in 20 (68.9 %) patients. Mutations in the CALR gene were detected in 4 (13.8 %) patients, mutations in the MPL gene were found in 3 patients (10.3 %). In 1 of 26 patients, 2 driver mutations were present simultaneously. 3 (10.3 %) patients were triple negative. Mutations in the ASXL1 gene were detected in 12 (41.4 %) out of 29 examined patients. Conducted targeted NGS (next generation sequencing) for 13 out of 29 patients revealed additional genetic variants that contribute to the understanding of the development mechanism and disease course. When evaluating the overall survival in the groups of patients diagnosed with MF examined by us, depending on the combination of driver (JAK2, CALR, MPL) and prognostic (ASXL1) mutations, no statistically significant differences were found (p = 0.12). This appears to be due to the small sample size. At the same time, assessment of patient survival depending on ASXL1 status showed that in the presence of mutations in the ASXL1 gene, the median survival was 45 months (range 7–120 months), while in the absence of mutations it was 48 months (range 21–359 months) (p = 0.03).Conclusion. The results obtained allow us to assume that the presence of mutations in the ASXL1 gene is an unfavorable factor in the course of the disease.
Aim. To study the association of nucleotide polymorphisms in platelet receptor and cytochrome P450 genes with the development of resistance to antiplatelet drugs in CHD patients.Material and Methods. The study included 243 patients diagnosed with CHD after coronary artery bypass surgery (CABG), including 140 patients in the acetylsalicylic acid (ASA) treatment group and 103 patients in the dual antiplatelet therapy (DAT) group. All patients were tested for platelet aggregation using an optical aggregometer with inducers: 5 mM ADP and 1 mM arachidonic acid (AA). DNA samples were analyzed by allele-specific PCR for the presence of polymorphisms rs2046934, rs1126643, rs5918, rs6065, rs4244285 in the platelet receptor and cytochrome P450 genes.Results. No statistically significant differences were found during comparison of the prevalence of the studied polymorphisms in the platelet receptor and cytochrome P450 genes between the groups of aspirin-sensitive and aspirin-resistant patients, as well as between the groups of clopidogrelsensitive and clopidogrel-resistant patients. No association between carriage of the minor and major alleles of the polymorphisms studied and the development of antiplatelet drug resistance was found. In the group of patients on ASA therapy, carriers of the C allele of the T1565C (rs5918) ITGB3 polymorphism had a higher rate of AA-induced platelet aggregation compared to carriers of the T allele (18,49±25,92 vs 10,43±17,34, р=0,004).Conclusion. Polymorphisms of P2RY12 (rs2046934), ITGA2 (rs1126643), ITGB3 (rs5918), GP1BA (rs6065), CYP2C19*2 (rs4244285) genes are not associated with antiplatelet drug resistance in both patients on ASC therapy and on DAT. The presence of minor alleles of the rs2046934, rs1126643, rs6065, rs4244285 polymorphisms are not associated with increased platelet aggregation activity before CABG.However, in the group of patients on ASA therapy C-allele carriers of the rs5918 polymorphism of the ITGB3 gene had a higher rate of AA-induced platelet aggregation compared to T-allele carriers.
Aim.To study the association of V640L (rs6133) polymorphism in the P-selectin gene with acetylsalicylic acid (ASA) resistance in patients with coronary heart disease after coronary bypass surgery (CABG).Material and methods.The study included 104 patients aged 36-78 years (mean age 61.6±6.9 years) with stable angina pectoris: 61 (58.7%) patients had functional class II (according to Canadian Cardiovascular Society), 41 (39.4%) – class III and 2 (1.9%) – class IV. Atherosclerotic lesions of the coronary arteries were confirmed by coronary angiography. The antiplatelet therapy was stopped for at least 5 days before CABG. In the postoperative period, from the first day, all patients received 100 mg of ASA in enteric form, 61 patients received alone ASA therapy, 43 patients – combined antiplatelet therapy: ASA+clopidogrel (75 mg/day). The aggregation study was performed with an optical aggregometer, using 5 μM adenosinediphosphate (ADP) and 1 mM arachidonic acid inductors before CABG, on 1-3 day and on 8-10 day after surgical treatment. DNA samples were examined for the V640L (rs6133) polymorphism in the P-selectin gene by real-time polymerase chain reaction (PCR) using the allele-specific primers.Results. The frequency of the homozygous GG genotype of the rs6133 polymorphism was 84.6%; heterozygous GT genotype – 15.4%. The amplitude of aggregation with ADP before CABG, on 1-3 day and on 8-10 day after CABG for carriers of homozygotes of allele G vs carriers of the allele T were: 47.9±19.3%, 44.5±17.8%, 30.1±13.2% vs 47.9±17.1%, 46.3±16.5%, 39.6±22.0%, respectively (p=0.497, 0.441 and 0.687, respectively). The amplitude of aggregation with arachidonic acid before CABG, on 1-3 day and on 8-10 day after CABG for carriers of homozygotesof allele G vs carriers of the allele T, were: 47.9±23.2%, 24.5±21.7%, 12.3±16.3% vs 54.3±17.8%, 29.7±23.7%, 11±10.9%, respectively (p=0.416, 0.825 and 0.872, respectively). In the first 10 days of the postoperative period, 6 thrombotic events (5.7%) were observed in the study group: 2 strokes and 4 perioperative myocardial infarctions. Five events occurred in the group of patients with the GG genotype, 1 event in the group of patients with the GT genotype.Conclusion. V640L (rs6133) polymorphism in the P-selectin gene is not associated with ASA resistance in patients with coronary artery disease after CABG. The T allele of the rs6133 polymorphism is not associated with increased platelet aggregation activity after CABG and does not increase the risk of adverse events in the first 10 days after CABG.
Aim. To study the association of T715P (rs6136), M62I (rs2228315), S290N (rs6131), V640L (rs6133) polymorphisms in the P-selectin gene with resistance to acetylsalicylic acid (ASA) in patients with coronary artery disease after coronary artery bypass grafting (CABG).Material and methods. The study included 90 patients aged 61,5±6,9 years (70 men and 20 women) with II-IV functional class (FC) angina pectoris, according to the Canadian Cardiovascular Society grading. The atherosclerotic nature of coronary artery disease is confirmed by coronary angiography. Patients stopped taking antiplatelet agents before CABG for at least 5 days. The aggregation study was carried out with an optical aggregometer using ADP inducers (5 pM) and arachidonic acid (1 µМ) before CABG, on 1-3 and 8-10 days after surgical treatment.DNA samples were examined for the presence of T715P (rs6136), M62I (rs2228315), S290N (rs6131), V640L (rs6133) polymorphisms in the P-selectin gene using realtime PCR with allele-specific primers.Results. When comparing aPTT, fibrinogen level, platelet aggregation activity with ADP inducers (5 µМ) and arachidonic acid (1 µМ), no differences were found among groups of patients with homozygous and heterozygous variants of the studied polymorphisms genotypes, both before and on 1-3, 8 -10 days after CABG. Regarding presence of ASA resistance, patient groups with homozygous variants of genotypes (T715P (rs6136), M62I (rs2228315), S290N (rs6131), V640L (rs6133)) did not statistically differ in prevailing or rare alleles from the corresponding groups with heterozygous genotypes. In the first 10 days of the postoperative period, thrombotic events (4,4%) were observed in 4 patients in the study group: acute myocardial infarction, acute cerebrovascular accident. Regarding frequency of adverse events in the first 10 days after CABG, between groups of patients with homozygous variants of the studied genotypes (T715P (rs6136), M62I (rs2228315), S290N (rs6131), V640L (rs6133) in prevailing allele and groups with heterozygous variants of the corresponding genotypes there were also no statistically significant differences.Conclusion. Rs6133, rs6163, rs2228315, rs6131 polymorphisms in the platelet P-selectin gene are not associated with ASA resistance and are not associated with increased platelet aggregation activity in patients with coronary artery disease. The rare T, C, G, A alleles of the studied polymorphisms do not lead to an increase in the risks of adverse events in the first 10 days after CABG.
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