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Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to...
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Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: 10 June 2026 | Viewed by 5369

Special Issue Editors

Dr. Lingfeng Luo

E-Mail Website
Guest Editor
Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
Interests: atherosclerosis; cardiovascular disease; cardio-oncology; and genetic epidemiology
Prof. Dr. Laurent Metzinger

E-Mail Website
Guest Editor
UR-UPJV 4666, HEMATIM, CURS, Université de Picardie Jules Verne, 80025 Amiens, France
Interests: gene regulation; non-coding RNAs; kidney disease; erythropoiesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular disease (CVD) remains a leading cause of global morbidity and mortality, with genetic and molecular factors playing pivotal roles in its development, progression, and treatment. Advances in genomics, transcriptomics, and epigenetics have revealed novel pathways and biomarkers, offering unprecedented opportunities in precision medicine. This Special Issue, "Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine", will showcase cutting-edge research and reviews exploring the genetic and molecular basis of CVD. Topics of interest include, but are not limited to, the following:

  • Genetic variants and pathways driving CVD risk and outcomes;
  • Epigenetic modifications (e.g., DNA methylation, histone modifications) in CVD pathogenesis;
  • The role of non-coding RNAs (e.g., miRNAs, lncRNAs) in cardiovascular biology;
  • Integration of polygenic risk scores (PRSs) and Mendelian randomization (MR) for causal inference and risk prediction;
  • Translational applications of genetic and molecular diagnostics in personalized CVD management (e.g., the sex gap in CVD).

We welcome original research articles, reviews, and perspectives exploring the genetic and molecular mechanisms behind CVD and their implications for precision medicine. This Special Issue will provide a platform for researchers to share insights into the genetic architecture of CVD and its potential in transforming clinical practice.

Dr. Lingfeng Luo
Prof. Dr. Laurent Metzinger
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiovascular disease
  • genetic variants
  • precision medicine
  • epigenetics
  • non-coding RNAs
  • polygenic risk scores
  • mendelian randomization
  • biomarkers
  • genome-wide association studies (GWASs)
  • molecular mechanisms

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Published Papers (7 papers)

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Research

Jump to: Review

22 pages, 3927 KB  
Article
Functional and Expression Studies of iPSC-Derived Cardiomyocytes Carrying a Novel HCM-Associated MYPN Genetic Variant
by Elena V. Dementyeva, Ekaterina S. Klimenko, Margarita Y. Sorokina, Anastasia K. Zaytseva, Maxim T. Ri, Ekaterina G. Nikitina, Dmitriy A. Kudlay, Anna M. Zlotina, Svetlana I. Tarnovskaya, Yuri V. Vyatkin, Dmitriy N. Shtokalo, Suren M. Zakian and Anna A. Kostareva
Genes 2026, 17(4), 456; https://doi.org/10.3390/genes17040456 - 14 Apr 2026
Viewed by 476
Abstract
Background/Objectives: Variants of MYPN, encoding a sarcomeric protein myopalladin, are associated with different types of cardiomyopathies and myopathies. However, the molecular mechanisms of MYPN-associated pathologies are still poorly understood. Methods: In this study, we generated induced pluripotent stem cells (iPSCs) from [...] Read more.
Background/Objectives: Variants of MYPN, encoding a sarcomeric protein myopalladin, are associated with different types of cardiomyopathies and myopathies. However, the molecular mechanisms of MYPN-associated pathologies are still poorly understood. Methods: In this study, we generated induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient carrying a novel p.N989I (c.2966A>T) variant of MYPN and used iPSC-derived cardiomyocytes to examine the impact of the variant on biophysical characteristics and transcriptomic profile. Results: No significant changes in parameters of calcium transients, sodium current and action potential were found in iPSC-derived cardiomyocytes with the p.N989I (c.2966A>T) variant of MYPN compared to non-isogenic cells from an unrelated healthy donor. At the transcriptomic level, MYPN-N989I cardiomyocytes demonstrated an upregulation of genes linked to cell cycle, mitotic spindle, microtubule cytoskeleton organization, and myogenic program genes. Downregulation of sarcomeric, Z-disc- and cell junction-associated genes, as well as genes involved in ATP synthesis, oxidative phosphorylation, and the SRF-signaling pathway, was also revealed. Conclusions: Our data suggest that the p.N989I (c.2966A>T) variant of MYPN plays a dual role in hypertrophic cardiomyopathy pathogenesis, disrupting not only sarcomeric and cytoskeletal organization but also the regulation of the muscle gene program. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
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12 pages, 2130 KB  
Article
Deciphering Silence: Functional Studies of GCK Synonymous and Nonsense Variants and Their Importance in Understanding Diabetes
by Concetta Aloi, Alessandro Salina, Serena Cappato, Nicola Minuto, Giuseppe D’Annunzio, Fabio Gotta, Davide Maggi, Paola Mandich, Laura Musso and Renata Bocciardi
Genes 2026, 17(2), 214; https://doi.org/10.3390/genes17020214 - 10 Feb 2026
Viewed by 598
Abstract
Background: The most common form of monogenic diabetes is maturity onset diabetes of the young (MODY). This study investigates the molecular basis of MODY type 2 (GCK-MODY) in a group of Italian patients, focusing on the functional characterization of a synonymous [...] Read more.
Background: The most common form of monogenic diabetes is maturity onset diabetes of the young (MODY). This study investigates the molecular basis of MODY type 2 (GCK-MODY) in a group of Italian patients, focusing on the functional characterization of a synonymous variant, c.579G>T (p.Gly193Gly), in the glucokinase gene (GCK). Methods: Clinical evaluation and genetic analysis, including whole exome sequencing and Sanger sequencing, were used to identify the variant in GCK, then functional studies using a minigene approach allowed the functional characterization. Results: This study identified the synonymous variant, along with a nonsense mutation, c.859C>T (p.Gln287Ter), in GCK in two Italian patients. Minigene approach demonstrated that the synonymous variant disrupts splicing at the exon 5 boundary, leading to a frameshift and premature stop codon. Similarly, the nonsense mutation also altered splicing, exacerbating the molecular defect. Conclusions: These findings highlight the importance of functional assays, particularly minigene studies, in interpreting the pathogenicity of synonymous and nonsense variants, especially in genes like GCK where splicing alterations can significantly impact protein function. This study underscores the clinical utility of targeted genetic screening for personalized diabetes management. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
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13 pages, 1416 KB  
Article
An ACOT4 Multi-Nucleotide Variant Is Associated with Cardiovascular Risk in Norfolk Island and UK Biobank Cohorts
by Jacob W. I. Meyjes-Brown, Heidi G. Sutherland, Kim Ngan Tran, Miles C. Benton, Rod A. Lea and Lyn R. Griffiths
Genes 2026, 17(2), 205; https://doi.org/10.3390/genes17020205 - 9 Feb 2026
Viewed by 726
Abstract
Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and [...] Read more.
Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and validate them in a general population cohort. Methods: We leveraged the population genetic features of the Norfolk Island Health Study (NIHS, n = 601), to identify candidate functional variants which were analysed for association with CVD and metabolic syndrome traits. We followed up suggestive variant-trait associations in the 2022 release of UK Biobank whole exome data (n = 200,625). Results: We identified a novel ten-base-pair in-frame missense multi-nucleotide variant (MNV), tagged by rs35724886, in the lipid metabolism gene ACOT4, which was associated with cholesterol levels and blood pressure. The MNV was associated with a lower incidence of ‘elevated BP’—systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg—(OR: 0.70; 95% CI: 0.51, 0.97; p = 0.03), and higher total cholesterol levels (β = 0.08; p = 0.04) in the NIHS. Validation in the UK Biobank revealed consistent associations between the MNV (proxied by rs35725886) and lower incidence of ‘elevated BP’ (p = 0.0001), higher total cholesterol (p = 0.01), and reduced use of medication for managing blood pressure (p = 1.8 × 10−6) and cholesterol (p = 0.002). Structural modelling and in-silico predictions suggested that the MNV introduced destabilising changes in the ACOT4 protein, likely influencing peroxisomal lipid metabolism pathways critical to CVD risk. Conclusions: This study identified a coding MNV with potential implications for understanding the genetic regulation of lipid metabolism and its impact on cardiovascular health. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
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9 pages, 221 KB  
Article
Sex- and Exercise-Dependent Modulation of Hypertrophic Remodeling by the MCT1 rs1049434 Polymorphism
by Natalia Fernández-Suárez, María Teresa Viadero, Teresa Amigo, José Antonio Benitez-Muñoz, Rocío Cupeiro and Domingo González-Lamuño
Genes 2026, 17(2), 188; https://doi.org/10.3390/genes17020188 - 2 Feb 2026
Viewed by 634
Abstract
Background: The monocarboxylate transporter 1 (MCT1) plays a central role in myocardial lactate handling and metabolic adaptation. The functional rs1049434 polymorphism (T1470A; Asp490Glu) affects MCT1-mediated lactate transport and substrate utilization, but its clinical relevance in sarcomere-related hypertrophic cardiomyopathy (HCM) remains poorly defined. Methods: [...] Read more.
Background: The monocarboxylate transporter 1 (MCT1) plays a central role in myocardial lactate handling and metabolic adaptation. The functional rs1049434 polymorphism (T1470A; Asp490Glu) affects MCT1-mediated lactate transport and substrate utilization, but its clinical relevance in sarcomere-related hypertrophic cardiomyopathy (HCM) remains poorly defined. Methods: We studied 56 carriers of pathogenic or likely pathogenic sarcomeric variants examined in a familial HCM program. All participants underwent standardized clinical phenotyping, including electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging. Genotyping of MCT1 rs1049434 was performed on genomic DNA. Analyses focused on sex-stratified genotype distribution, phenotypic expression among the 26 individuals who fulfilled diagnostic criteria for HCM, and the influence of habitual vigorous exercise. Septal wall thickness was the primary structural endpoint. Results: Among the 26 patients with established HCM (10 women, 16 men), a marked sex-specific effect emerged. Female carriers of the T-allele (TT/TA) exhibited significantly greater interventricular septal thickness compared with AA homozygotes (23.2 vs. 14.2 mm; p = 0.037). In men, septal thickness did not differ by genotype. However, male patients engaged in vigorous physical activity showed a consistently milder structural phenotype, including lower septal thickness (18.3 vs. 19.9 mm; p = 0.585) and directionally favorable markers of mechanical severity. Phenotypic distribution was predominantly asymmetric septal hypertrophy in both sexes, without genotype-dependent differences. Conclusions: The phenotypic impact of MCT1 rs1049434 in sarcomere-positive HCM is context-dependent. In women, impaired monocarboxylate handling is associated with greater hypertrophic remodeling, whereas in men, exercise-related metabolic conditioning appears to attenuate disease severity. These findings support a genotype–sex–environment interaction relevant to precision medicine approaches in HCM. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
10 pages, 216 KB  
Article
Association of Gene Polymorphism at Atrial Fibrillation in the Kazakh Population: Case—Control Study
by Dana Taizhanova, Nazira Bazarova, Akerke Kalimbetova, Roza Bodaubay, Elena Zholdybayeva and Chingis Abylkanov
Genes 2026, 17(1), 84; https://doi.org/10.3390/genes17010084 - 13 Jan 2026
Viewed by 541
Abstract
Background/Objectives. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and represents a major public health problem. Genetic factors contribute to AF susceptibility, including variants associated with atrial remodeling. Methods. This case–control study investigated the rs3903239 polymorphism of the PRRX1 gene in [...] Read more.
Background/Objectives. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and represents a major public health problem. Genetic factors contribute to AF susceptibility, including variants associated with atrial remodeling. Methods. This case–control study investigated the rs3903239 polymorphism of the PRRX1 gene in a Kazakh population. The main group included patients with AF (n = 75), the control group consisted of 2 subgroups: subgroup 1 (control group 1) included conditionally healthy patients (n = 73), subgroup 2 (control group 2) consisted of patients with arterial hypertension (AH) and coronary heart disease (CHD) without diagnosed AF at the time of inclusion in the study (n = 50). Genotype and allele frequencies were compared between patients with AF and two control groups. The frequency of the rs3903239 polymorphism genotypes of the PRRX1 gene in the main group and in the control groups was in the Hardy–Weinberg equilibrium. Results. The frequency of the rare G allele (AG + GG genotypes) was higher in patients with AF compared with conditionally healthy controls; however, this difference did not reach statistical significance (OR 1.357; 95% CI 0.845–2.178). Conclusions. The observed differences represent a non-significant trend and do not demonstrate a statistically confirmed association between the rs3903239 polymorphism of the PRRX1 gene and AF in the Kazakh population. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)

Review

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22 pages, 1377 KB  
Review
High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN and Desmosomal Genes in the ESC 2023 Era
by Nardi Tetaj, Andrea Segreti, Aurora Ferro, Virginia Ligorio, Alberto Spagnolo and Francesco Grigioni
Genes 2026, 17(4), 370; https://doi.org/10.3390/genes17040370 - 25 Mar 2026
Cited by 2 | Viewed by 849
Abstract
Inherited cardiomyopathies represent a major cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), frequently occurring in the absence of advanced systolic dysfunction. Traditional strategies for the primary prevention of SCD have relied predominantly on left ventricular ejection fraction (LVEF), an approach [...] Read more.
Inherited cardiomyopathies represent a major cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), frequently occurring in the absence of advanced systolic dysfunction. Traditional strategies for the primary prevention of SCD have relied predominantly on left ventricular ejection fraction (LVEF), an approach that fails to capture the substantial biological and clinical heterogeneity of non-ischemic cardiomyopathies. Over the past decade, advances in cardiac genetics and cardiac magnetic resonance imaging have identified specific genotypes associated with a disproportionate arrhythmic risk, which often precedes overt ventricular remodeling. The 2023 European Society of Cardiology (ESC) Guidelines on cardiomyopathies formalize this paradigm shift by integrating etiology, myocardial substrate, and electrical phenotype into contemporary risk stratification. In this narrative review, we focus on cardiomyopathy-associated genotypes consistently linked to high arrhythmic risk—LMNA, truncating variants in FLNC, RBM20, PLN p.Arg14del, and desmosomal genes—and examine their molecular mechanisms, phenotypic trajectories, and arrhythmogenic profiles. We discuss how genotype-specific patterns of myocardial fibrosis, conduction disease, and VA inform implantable cardioverter-defibrillator (ICD) decision-making beyond LVEF-based thresholds. By synthesizing genetic, imaging, and clinical evidence in light of ESC 2023 recommendations, this review highlights the evolving role of genotype-informed strategies in the personalized prevention of SCD and underscores remaining gaps in evidence and risk prediction. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
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26 pages, 393 KB  
Review
Genetic Mutations Underlying Growth Impairment and Cardiomyopathies in Children: Molecular Mechanisms, Clinical Implications and Targeted Therapies
by Marco Maria Dicorato, Gaia De Sario, Maria Cristina Carella, Andrea Igoren Guaricci, Marco Matteo Ciccone, Cinzia Forleo, Gabriele D’Amato and Maria Felicia Faienza
Genes 2026, 17(3), 355; https://doi.org/10.3390/genes17030355 - 23 Mar 2026
Viewed by 739
Abstract
Growth impairment is a clinical manifestation frequently observed in pediatric patients with cardiomyopathy associated with various inherited disorders, including RASopathies, lysosomal storage diseases, neuromuscular disorders, and metabolic conditions. In this narrative review, we explored the genetic and pathophysiological mechanisms underlying the development of [...] Read more.
Growth impairment is a clinical manifestation frequently observed in pediatric patients with cardiomyopathy associated with various inherited disorders, including RASopathies, lysosomal storage diseases, neuromuscular disorders, and metabolic conditions. In this narrative review, we explored the genetic and pathophysiological mechanisms underlying the development of both growth and myocardial impairment in Noonan syndrome (NS)—the most common RASopathy—Duchenne and Becker muscular dystrophies, Pompe disease, mucopolysaccharidoses, and mitochondrial diseases. For each condition, we described the cardiac and growth phenotypes, focusing on epidemiology, clinical implications, and disease-specific therapeutic strategies. In the era of precision medicine, innovative etiologic treatments targeting the underlying molecular mechanisms have emerged. Therefore, elucidating the molecular pathways responsible for growth impairment in pediatric inherited cardiomyopathies remains essential for optimizing multidisciplinary management and improving patient outcomes. Full article
(This article belongs to the Special Issue Genetic and Molecular Insights into Cardiovascular Disease: From Mechanisms to Precision Medicine)
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