International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 44 2.2 Contributions of single-gene and polygenic factors Single-gene mutations have been identified as significant contributors to familial hypertensive heart disease. For instance, mutations in MYH7 and ACTC1 are well-documented in hypertrophic cardiomyopathy, a condition often associated with hypertension (Blair et al., 2001). Additionally, mutations in the BMPR2 gene have been linked to familial primary pulmonary hypertension, highlighting the role of single-gene defects in specific hypertensive conditions. Polygenic influences are also substantial, with GWAS identifying numerous loci associated with blood pressure and hypertension. For example, a meta-analysis identified 30 new genetic regions, including rare missense variants in RBM47, COL21A1, and RRAS, which have larger effects on blood pressure than common variants (Surendran et al., 2016). Another large-scale GWAS identified 535 novel loci associated with blood pressure, underscoring the complex polygenic nature of hypertension (Warren et al., 2018). These studies reveal that while single-gene mutations can have significant impacts, the cumulative effect of multiple genetic variants also plays a crucial role in disease manifestation. 2.3 Epigenetic factors and gene-environment interactions Epigenetic factors, including DNA methylation, histone modifications, and non-coding RNAs, are increasingly recognized for their roles in the progression of hypertensive heart disease. These modifications can influence gene expression and thereby affect blood pressure regulation and cardiac function. For instance, gene expression profiles associated with blood pressure have identified differentially expressed genes involved in inflammatory response and apoptosis pathways, suggesting that epigenetic regulation is a key component in hypertension (Huan et al., 2015). Environmental factors interact with genetic backgrounds to contribute to hypertensive heart disease. Lifestyle factors such as diet, physical activity, and exposure to stress can modify the expression of hypertension-related genes. For example, genetic loci associated with blood pressure have shown pleiotropic associations with lifestyle exposures, including dietary intake of salt, caffeine, and alcohol (Warren et al., 2018). This gene-environment interaction highlights the importance of considering both genetic predispositions and environmental influences in understanding and managing hypertensive heart disease. 3 Key Gene Mutations Associated with FHH 3.1 Ion channel gene mutations Mutations in the SCN5A and KCNQ1 genes significantly impact myocardial electrical conduction, leading to various arrhythmias. The SCN5A gene encodes the cardiac sodium channel Nav1.5, and mutations such as M1875T have been associated with increased atrial excitability and familial Atrial Fibrillation (AF) (Makiyama et al., 2008; O’Reilly et al., 2022). These mutations result in a gain-of-function, causing a pronounced depolarized shift in the voltage dependence of steady-state inactivation, which increases atrial excitability (Makiyama et al., 2008). Similarly, KCNQ1 mutations, such as R231C, can cause both long QT syndrome type 1 (LQT1) and familial AF by altering the potassium channel's function, leading to constitutively active currents and smaller maximal currents (Bartos et al., 2011). Ion channel mutations can lead to myocardial fibrosis and arrhythmias by disrupting the normal electrical signaling in the heart. For instance, SCN5A mutations are linked to arrhythmic dilated cardiomyopathy (DCM), where the disruption in the voltage-sensing mechanism of the sodium channel leads to a high incidence of arrhythmias, including atrial fibrillation and ventricular tachycardia (McNair et al., 2011). These electrical disturbances can promote structural remodeling of the myocardium, contributing to fibrosis and further exacerbating arrhythmic conditions. 3.2 Cardiac structural gene mutations Mutations in the MYH7 gene, which encodes the beta-cardiac myosin heavy chain, are well-documented in Familial Hypertrophic Cardiomyopathy (FHC). For example, the Arg663His mutation in MYH7 is associated with significant left ventricular hypertrophy, particularly in the proximal segment of the interventricular septum. This
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