New Epigenetic Markers of Age-Dependent Changes in the Cardiovascular System

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Abstract

Cardiovascular diseases remain a predominant global cause of mortality, with a noteworthy rise in the risk of morbidity with advancing age. Besides, it accompanied by a phenomenon of disease rejuvenation in the circulatory system. Currently, epigenetic modifications play a key role in the genesis of cardiovascular diseases (CVD), influencing the complex interaction between genotype and phenotype variability. Consequently, delving into the realm of epigenetic markers offers a promising avenue to unravel the molecular underpinnings of cardiovascular disease pathogenesis. This study endeavors to pinpoint epigenetic markers intricately linked with age-related transformations in the cardiovascular system. The study revealed a robust correlation with age for two cardiological parameters: R wave tension in the augmented left arm lead (RaVL) and carotid-femoral pulse wave velocity (cfPWV). Moreover, these parameters exhibited a strong correlation with the DNA methylation level of 21 CpG-sites (CpGs) examined through the Illumina EPIC array. Notably, the majority of these identified CpG-sites are affiliated with genes involved in the development of pathologies of the cardiovascular system.

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About the authors

L. M. Ermakova

Lobachevsky Nizhny Novgorod State University

Email: spring_dusk@mail.ru
Russian Federation, Nizhny Novgorod, 603022

E. A. Davydova

Lobachevsky Nizhny Novgorod State University

Author for correspondence.
Email: spring_dusk@mail.ru
Russian Federation, Nizhny Novgorod, 603022

E. V. Kondakova

Lobachevsky Nizhny Novgorod State University

Email: spring_dusk@mail.ru
Russian Federation, Nizhny Novgorod, 603022

K. V. Kuchin

Clinical Hospital No. 38

Email: spring_dusk@mail.ru
Russian Federation, Nizhny Novgorod, 603000

M. V. Vedunova

Lobachevsky Nizhny Novgorod State University

Email: spring_dusk@mail.ru
Russian Federation, Nizhny Novgorod, 603022

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3. Fig. 1. Spearman correlation matrix, which represents the correlation coefficients between the functional parameters of the cardiovascular system and the age values obtained using various models, including chronological, epigenetic and biological age (n = 48). Epigenetic and biological age were calculated using the following models: DNAmAgeHannum [19], DNAmAge [11], DNAmPhenoAge [20], DNAGrimAge [21] and PhenoAge [20]. The p values associated with the correlation coefficients are shown in Table S1 (see Additional materials in electronic form according to the DOI of the article and on the website http://www.molecbio.ru/downloads/2024/6/supp_Ermakova_rus.rar).

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4. Fig. 2. The relationship between CFS, RaVL, and chronological, biological, and epigenetic age (n = 48). Here and further: along with the regression line, the graphs show the values of the Spearman correlation coefficient (r) and p-value (p).

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5. Fig. 3. The relationship between CFS and the level of methylation of individual CpG sites (n = 48). DNA methylation levels were assessed using the Illumina Infinium MethylationEPIC BeadChip technology.

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6. Fig. 4. The relationship between RaVL and the methylation level of individual CpG sites (n = 48).

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7. Fig. 5. Schematic representation of the links found in the scientific literature between functional cardiological parameters, genes and pathologies of the cardiovascular system. Designations: GCM — hypertrophic cardiomyopathy, GM — myocardial hypertrophy, coronary artery disease ‒ coronary artery disease, MI — myocardial infarction, KMP — cardiomyopathy, DM2 — type 2 diabetes mellitus. The pink rectangles indicate the indicators of the cardiovascular system that are most associated with age according to the results of our study. Yellow ovals indicate genes containing CpG sites, the level of methylation of which was highly correlated with the selected indicators of the cardiovascular system. The green ovals indicate pathologies associated with the studied genes and CpG sites. The black arrows indicate direct links between the studied parameters, genes, and diseases. Dotted lines indicate an indirect connection. The diagram was created using the LibreOffice Draw editor.

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