CLONAL HEMATOPOIESIS WITH INDETERMINATE POTENTIAL IN TET2 AND DNMT3A AMONG KAZAKHSTANI INDIVIDUALS WITH ATHEROSCLEROTIC DISEASE
Purpose of the study: To assess the contribution of clonal hematopoiesis of indeterminate potential (CHIP) to the development of atherosclerotic disease in the Kazakhstani cohort, focusing on TET2 and DNMT3A genes, based on next-generation sequencing (NGS) data.
Materials and Methods: This study employed an observational cross-sectional design. The cohort comprised 177 women and 225 men, with a mean age of 53.0 ± 9.04 years overall (men: 52.2 ± 9.0 years; women: 53.7 ± 9.0 years). Patients were stratified by degree of cardiovascular risk category (low, high, very high) according to the ESC/EAS (2019) recommendations. In this sample, 74 participants (18.4%) were classified as low-risk, 136 (33.8%) as high-risk, and 192 (47.8%) as very high-risk. For the initial phase of analysis, the two most studied genes, TET2 and DNMT3A, were selected from a total list of 8 priority genes: ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SFRS2, TET2, and TP53 associated with CHIP, based on their high clinical significance and frequency of occurrence in previously published studies. By filtering the data and selecting two priority genes for primary analysis, 41 patients with atherosclerotic disease were selected from the total cohort. Genetic analyses were performed using high-throughput whole-exome sequencing to cover a wide range of genetic variants potentially associated with CHIP and the atherosclerotic process. Variant annotation was performed using international databases (ClinVar, ExAC, 1000 Genomes, etc.), and mutations were interpreted according to the ACMG/AMP classification using the InterVar platform. Statistical data processing included the nonparametric Kruskal-Wallis test, Dunn's test for pairwise comparisons, and Fisher's exact test; a value of p < 0.05 was considered statistically significant.
Results: Variants were detected in TET2 (n=35) and DNMT3A (n=6). The median VAF value for TET2 was 50%. The age of patients differed significantly between risk groups (p = 0.026). Most of the variants detected had an ultra-rare frequency according to international databases (<0.1%). One pathogenic variant was identified according to the InterVar classification; the others were predominantly of uncertain significance (VUS). The distribution of variants by risk groups showed no statistically significant differences (p = 0.341).
Conclusions: The results demonstrate a potential role of CHIP-associated mutations in the pathogenesis of atherosclerosis. Mutations in TET2 were found to be the most significant. Given the identified genetic features and their association with cardiovascular risk, the findings justify extending the analysis to the full spectrum of CHIP-associated genes to improve the accuracy of risk stratification.
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Bekbossynova M.S., Shakhmarova T.K., Mirmanova Zh.Zh., Zhalbinova M.R. , Chamoieva A.E., Satvaldina N.N., Rakhimova S.E., Yerezhepov D.A., Kairov U.E., Daniyarov A.Zh., Andossova S.A., Ivanova-Razumova T.V., Sailybayeva A.I., Khamitov S.R., Akilzhanova A.R. Clonal Hematopoiesis with Indeterminate Potential in TET2 and DNMT3A among Kazakhstani Individuals with Atherosclerotic Disease // Nauka i Zdravookhranenie [Science & Healthcare]. 2025. Vol.27 (5), pp. 16-23. doi 10.34689/SH.2025.27.5.002Related publications:
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