Atherosclerosis
Atherosclerosis is a chronic inflammatory disease characterized by the progressive buildup of plaques within the inner lining of arteries, known as the intima[1]. This complex process involves the accumulation of lipids, immune cells, and fibrous tissue, leading to the hardening and narrowing of arteries. Early and subclinical manifestations, such as increased carotid intima-media thickness (CIMT) and the presence of arterial plaque, are often used to assess the disease’s initiation and progression[2], [3], [4], [5], [6].
The biological basis of atherosclerosis is multifaceted, arising from an interplay of genetic predispositions and environmental factors. Research indicates that specific genetic variants are associated with key indicators of the disease, such as CIMT and plaque formation[2]. Genome-wide association studies (GWAS) have identified common variants linked to carotid intima-media thickness and plaque [2], and specific genetic loci, like a 3’UTR variant of RARB, have been associated with CIMT [5]. Conversely, protective genetic variations, such as those found in the CETPgene, can influence cardiovascular resilience[7]. Furthermore, gene-environment interactions, exemplified by the link between the PIGR-FCAMRlocus and coronary atherosclerosis in the context of residential traffic exposure, highlight the complex etiology of the condition[8]. Novel pathways, including taste transduction, are also being explored for their potential role in carotid plaque development [3].
Clinically, atherosclerosis is the primary underlying cause of atherosclerotic cardiovascular disease (ASCVD)[7]. This encompasses a range of severe health conditions, including coronary atherosclerosis, ischemic heart disease (IHD), stroke, and carotid artery stenosis[5], [9], [10], [8]. The presence of carotid plaque and increased CIMT are recognized as significant predictors of future cardiovascular events[4]. Medical management strategies, often involving cholesterol-lowering medications like statins, are critical for slowing disease progression and mitigating associated risks[7].
Atherosclerosis holds significant social importance due to its profound impact on global public health. As a leading cause of cardiovascular disease, it contributes substantially to morbidity, disability, and mortality worldwide. The extensive research efforts, including large-scale meta-analyses from consortia like CHARGE and multi-ancestry GWAS involving hundreds of thousands of individuals, underscore the widespread prevalence and immense societal burden of atherosclerosis, driving continuous scientific investigation into its genetic and environmental determinants and the development of effective interventions[2], [9].
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Research into atherosclerosis, particularly through genome-wide association studies (GWAS), faces several methodological and statistical limitations that impact the comprehensiveness and interpretation of findings. While large sample sizes in meta-analyses enhance statistical power for common variants, studies often still have limited power to detect associations with small effect sizes, which are characteristic of complex traits[2]. Furthermore, commercial genotyping arrays used in GWAS are primarily designed to detect common variants and may miss rarer genetic variants that contribute to disease risk, leading to an incomplete picture of genetic architecture. The sparse coverage or varying imputation quality in certain genomic regions, such asAPOC1 and LDLR, can also reduce the effective sample size and hinder the discovery of associations in these areas[2].
Another significant constraint is the frequent lack of independent replication cohorts, which is crucial for confirming initial findings and bolstering confidence in identified associations, especially when genome-wide significance is achieved only in combined meta-analyses [2]. Many identified single nucleotide polymorphisms (SNPs) are likely not the causal variants themselves but are in linkage disequilibrium with unanalyzed causal variants, necessitating further fine-mapping and functional studies to pinpoint the true etiological drivers[2]. The use of approximate conditional analysis based on ancestry-matched linkage disequilibrium (LD) matrices, while useful, also introduces assumptions that might not perfectly reflect the LD patterns in all study populations, potentially affecting the accuracy of identifying independent signals [4].
Phenotypic Heterogeneity and Generalizability
Section titled “Phenotypic Heterogeneity and Generalizability”A key challenge in atherosclerosis research stems from the heterogeneity in phenotype definition and measurement protocols across different studies. For instance, carotid intima-media thickness (cIMT) assessments are often cross-sectional, and ultrasound protocols, including plaque definitions (e.g., presence of any plaque versus stenosis greater than 25%), can vary considerably among participating cohorts[2]. Such inconsistencies in measurement techniques may compromise the ability to detect subtle genetic associations and complicate the meta-analysis of results. Additionally, while measures like the number of diseased coronary vessels provide insights into clinically significant atherosclerosis, they may not capture subclinical atherosclerosis, which can also be influenced by genetic and environmental factors[8].
The generalizability of findings is another critical limitation, as many large-scale genetic discovery efforts initially focus on populations of European ancestry [2]. While this approach helps mitigate population stratification within discovery cohorts, it can limit the direct applicability of findings to diverse populations due to differences in allele frequencies, linkage disequilibrium patterns, and environmental exposures [8]. Replication and validation in additional independent populations of varied ethnicities are therefore essential to ensure the broader relevance of identified genetic associations.
Complex Etiology and Unresolved Factors
Section titled “Complex Etiology and Unresolved Factors”Atherosclerosis is a complex disease influenced by a multitude of genetic and environmental factors, and current research still grapples with fully elucidating its intricate etiology. While studies have begun to identify gene-environment interactions, such as genetic variants interacting with residential exposure to traffic, the full spectrum of environmental confounders and their interplay with genetic predispositions remains largely unexplored[8]. Many genetic variants identified to date explain only a modest proportion of the heritability of atherosclerosis-related traits, indicating a significant “missing heritability” that may be attributed to rare variants, more complex gene-gene or gene-environment interactions, or epigenetic factors not typically captured by standard GWAS[6].
Furthermore, despite advancements in identifying genetic loci, a substantial knowledge gap persists regarding the precise biological mechanisms through which these variants contribute to atherosclerosis. The initial identification of associations often necessitates extensive follow-up with dense genotyping, expression studies, and translational research to understand the functional consequences of genetic variation[2]. Without such detailed mechanistic insights, the full translational potential of genetic discoveries for prevention and treatment strategies remains limited.
Variants
Section titled “Variants”Genetic variants play a significant role in an individual’s susceptibility to atherosclerosis, a chronic inflammatory disease characterized by plaque buildup in arteries. These variants can influence lipid metabolism, vascular cell function, inflammation, and other pathways contributing to disease development.
Several genetic loci linked to lipid metabolism are crucial in atherosclerosis. The cholesteryl ester transfer protein (CETP) gene is a prime example, with variants like rs183130 affecting the protein’s activity, which in turn alters plasma levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Research indicates that carriers of rare protein-truncating variants inCETPoften display higher HDL-C, lower LDL-C, and a reduced risk of atherosclerotic cardiovascular disease (ASCVD), suggesting that naturally occurring genetic inhibition of CETP can protect against ASCVD[7]. The LPAgene, encoding lipoprotein(a) (Lp(a)), is another key player; its variants, includingrs74617384 , rs55730499 , and rs10455872 , are associated with elevated Lp(a) levels, a strong independent risk factor for atherosclerosis. Specifically, thers10455872 variant has been significantly associated with carotid artery atherosclerotic disease, highlighting its impact on subclinical atherosclerosis[10]. Additionally, the low-density lipoprotein receptor (LDLR) gene, essential for clearing LDL cholesterol from the blood, also harbors variants such as rs12151108 , rs61194703 , and rs77140532 . Genetic variations near LDLRhave been identified as novel loci linked to carotid plaque, underscoring its foundational role in lipid pathways and coronary heart disease[4].
Beyond lipid regulation, variants in genes affecting cell cycle control and vascular integrity contribute to atherosclerosis. TheCDKN2B-AS1 gene, located in the well-known 9p21 region, produces a long non-coding RNA that modulates the expression of adjacent tumor suppressor genes, CDKN2A and CDKN2B. These genes are vital for regulating cell proliferation and senescence in vascular smooth muscle cells, processes critical to the formation and progression of atherosclerotic plaques. Variants likers1333049 and rs1333047 within this region have been associated with carotid intima-media thickness (cIMT) and carotid plaque, reflecting their influence on arterial wall health [4]. The 9p21 locus is widely recognized as a robust genetic risk factor for various forms of subclinical atherosclerosis[2]. Furthermore, the HDAC9gene, encoding histone deacetylase 9, impacts chromatin structure and gene expression, influencing vascular smooth muscle cell differentiation and migration—key events in arterial remodeling and plaque development. Variants such asrs2107595 in the HDAC9 - TWIST1region have been implicated in large vessel disease, suggesting a role in the structural changes of the arterial wall.
Other genetic influences on atherosclerosis include those related to neurological function, smoking behavior, and non-coding RNA regulation. Variants inCHRNA5 (e.g., rs17486278 ) and CHRNA3 (e.g., rs8040868 , rs12914385 ) encode subunits of nicotinic acetylcholine receptors, which are strongly associated with nicotine dependence. By influencing an individual’s smoking habits, these variants indirectly contribute to atherosclerosis, as smoking is a primary risk factor. TheATXN2 gene, while primarily known for neurodegenerative conditions, has variants like rs4766578 that are linked to metabolic traits such as type 2 diabetes and obesity, which are significant risk factors for cardiovascular disease. Additionally, non-coding regions, includingLINC02356 (rs10774624 ) and the DNAJC8P3 - MIR4472-1 locus (rs566179233 ), are gaining recognition for their regulatory roles in gene expression and cellular processes relevant to vascular inflammation and disease. Genome-wide association studies have been instrumental in identifying numerous loci associated with subclinical atherosclerosis, providing a comprehensive view of the genetic architecture of this complex disease[6].
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1333049 rs1333047 | CDKN2B-AS1 | coronary artery disease coronary artery calcification stroke, coronary artery disease large artery stroke, coronary artery disease total cholesterol measurement, hematocrit, stroke, ventricular rate measurement, body mass index, atrial fibrillation, high density lipoprotein cholesterol measurement, coronary artery disease, diastolic blood pressure, triglyceride measurement, systolic blood pressure, heart failure, diabetes mellitus, glucose measurement, mortality, cancer |
| rs183130 | HERPUD1 - CETP | high density lipoprotein cholesterol measurement metabolic syndrome total cholesterol measurement low density lipoprotein cholesterol measurement, phospholipids:total lipids ratio intermediate density lipoprotein measurement |
| rs74617384 rs55730499 rs10455872 | LPA | parental longevity apolipoprotein B measurement total cholesterol measurement serum creatinine amount glomerular filtration rate |
| rs2107595 | HDAC9 - TWIST1 | coronary artery disease Ischemic stroke pulse pressure measurement stroke systolic blood pressure |
| rs17486278 | CHRNA5 | forced expiratory volume, response to bronchodilator FEV/FVC ratio, response to bronchodilator pulmonary function measurement pulmonary artery enlargement, chronic obstructive pulmonary disease emphysema pattern measurement |
| rs566179233 | DNAJC8P3 - MIR4472-1 | atherosclerosis |
| rs10774624 | LINC02356 | rheumatoid arthritis monokine induced by gamma interferon measurement C-X-C motif chemokine 10 measurement Vitiligo systolic blood pressure |
| rs4766578 | ATXN2 | reticulocyte count Vitiligo smoking initiation coronary artery disease gout |
| rs8040868 rs12914385 | CHRNA3 | forced expiratory volume FEV/FVC ratio forced expiratory volume, response to bronchodilator FEV/FVC ratio, response to bronchodilator FEV/FVC ratio, pulmonary function measurement, smoking behavior trait |
| rs12151108 rs61194703 rs77140532 | SMARCA4 - LDLR | total cholesterol measurement low density lipoprotein cholesterol measurement choline measurement cholesterol:total lipids ratio, blood VLDL cholesterol amount, chylomicron amount esterified cholesterol measurement |
Defining Atherosclerosis and its Core Concepts
Section titled “Defining Atherosclerosis and its Core Concepts”Atherosclerosis is precisely defined as an inflammatory disease characterized by the buildup of plaque within the arteries[1]. This chronic condition leads to the hardening and narrowing of arteries, which can impede blood flow and has significant clinical implications. The broader term, atherosclerotic cardiovascular disease (ASCVD), encompasses the various clinical manifestations arising from atherosclerosis[7]. Understanding atherosclerosis conceptually involves recognizing its progressive nature, starting often in early life and advancing over decades, contributing to a substantial burden of cardiovascular morbidity and mortality.
Classification by Arterial Territory and Clinical Presentation
Section titled “Classification by Arterial Territory and Clinical Presentation”Atherosclerosis is classified not only by its underlying pathology but also by its location within the body and its clinical stage. It can affect multiple “major arterial territories,” including the coronary arteries, carotid arteries, abdominal aorta, and peripheral arteries, each with distinct clinical consequences[6]. This anatomical classification is critical for diagnosis and management, differentiating conditions like coronary atherosclerosis[8], carotid artery stenosis [10], or peripheral arterial disease. Furthermore, atherosclerosis is categorized into “subclinical atherosclerosis,” which refers to the presence of arterial changes before overt symptoms appear, and “clinically apparent cardiovascular disease,” where symptoms and events such as myocardial infarction or stroke are evident[6]. The identification of subclinical forms, such as carotid plaque [2], is vital for early risk assessment and intervention.
Measurement and Diagnostic Criteria for Subclinical Atherosclerosis
Section titled “Measurement and Diagnostic Criteria for Subclinical Atherosclerosis”The diagnosis and severity gradation of atherosclerosis, particularly in its subclinical stages, rely on several standardized measurement approaches and criteria. Key measures include carotid intima-media thickness (cIMT) and carotid plaque, assessed via carotid ultrasound, which can identify subclinical vascular disease and predict future cardiovascular events[2]. Coronary artery calcification (CAC) and abdominal aortic calcification (AAC) are measured using multidetector computed tomography (MDCT), with a calcified lesion operationally defined as an area of at least three connected pixels with CT attenuation greater than 130 Hounsfield Units[6]. These calcification scores, often based on modifications of the Agatston Score, are crucial indicators that predict cardiovascular disease risk independently of traditional risk factors[6]. Another important diagnostic tool is the ankle-brachial index (ABI), derived from ankle-brachial systolic blood pressure measurements, which is used to detect peripheral arterial disease and also serves as a predictor of future cardiovascular outcomes[11].
Causes
Section titled “Causes”Atherosclerosis, a complex progressive disease characterized by the hardening and narrowing of arteries, results from a multifaceted interplay of genetic predispositions, environmental exposures, and systemic physiological factors. Its development is not attributed to a single cause but rather a cumulative effect of various contributing elements over time.
Genetic Foundations
Section titled “Genetic Foundations”Genetic factors significantly contribute to an individual’s susceptibility to atherosclerosis. Large-scale genetic studies, such as genome-wide association studies (GWAS) conducted by consortia like CHARGE and the Framingham Heart Study, have identified numerous common genetic variants and loci associated with subclinical atherosclerosis measures like carotid intima-media thickness (CIMT) and plaque formation[2]. For instance, specific genetic variations, including those in the CETPgene, have been identified as protective against atherosclerotic cardiovascular disease, while a 3’UTR genetic variant ofRARBhas been linked to CIMT, particularly in the context of rheumatoid arthritis[7]. The disease’s polygenic nature means that many genes, each with a small effect, collectively influence risk, potentially involving gene-gene interactions and pathways such as taste transduction, which has been suggested for carotid plaque development[3].
Environmental Exposures and Gene-Environment Interplay
Section titled “Environmental Exposures and Gene-Environment Interplay”Beyond inherited predispositions, environmental factors play a crucial role in triggering and accelerating atherosclerosis. Exposure to certain external elements can significantly impact disease progression, especially when interacting with an individual’s genetic makeup. For example, residential exposure to traffic has been identified as an environmental trigger that, in combination with specific genetic variants at thePIGR-FCAMRlocus, is linked to coronary atherosclerosis[8]. This highlights how an individual’s living environment can interact with their genetic profile to modulate the risk and severity of the disease.
Inflammatory Processes and Co-existing Conditions
Section titled “Inflammatory Processes and Co-existing Conditions”Atherosclerosis is fundamentally understood as an inflammatory disease, where chronic inflammation within the arterial walls drives plaque formation and progression[1]. This inflammatory state can be exacerbated by various co-existing medical conditions, known as comorbidities. Rheumatoid arthritis, an autoimmune inflammatory disease, serves as a notable example, where its systemic inflammation is associated with an increased risk and progression of atherosclerosis, evidenced by links to carotid intima-media thickness[5]. Thus, the presence of other inflammatory or metabolic disorders can significantly contribute to the development and worsening of atherosclerotic plaques by perpetuating a pro-inflammatory environment.
Age and Therapeutic Modulators
Section titled “Age and Therapeutic Modulators”Age is an undeniable and significant non-modifiable risk factor for atherosclerosis, with the disease’s prevalence and severity increasing steadily with advancing years. Research studies frequently adjust for age, underscoring its independent contribution to the accumulation of arterial damage and plaque over a lifetime[7]. Furthermore, the impact of various therapeutic interventions, such as cholesterol-lowering medications like statins, is also considered in the broader context of atherosclerosis. While these medications are used to treat or manage the disease, their effects are often accounted for in research to isolate other causal factors, indicating their substantial influence on the disease’s trajectory[7].
Biological Background
Section titled “Biological Background”Atherosclerosis is a chronic inflammatory disease characterized by the progressive buildup of fatty plaques within the inner lining of arteries, leading to their hardening and narrowing[1]. This condition disrupts the normal elasticity and function of blood vessels, impeding blood flow and increasing the risk of severe cardiovascular complications. The development of atherosclerosis is a complex process influenced by a combination of genetic predispositions, cellular and molecular pathways, and environmental factors.
Pathophysiology and Clinical Manifestations
Section titled “Pathophysiology and Clinical Manifestations”Atherosclerosis begins as a subclinical condition, often detectable through measures like carotid intima-media thickness (CIMT) and the presence of carotid plaque[2], [6], [4]. These early structural changes in arterial walls signify a disruption in vascular homeostasis and can progress silently over many years. As the disease advances, plaque accumulation can lead to significant arterial narrowing, such as carotid artery stenosis[10], which severely restricts blood flow and oxygen delivery to tissues.
The systemic nature of atherosclerosis means it can affect various major arterial territories, including coronary arteries, carotid arteries, and arteries in the lower extremities[6], [8]. The clinical manifestations are diverse and depend on the affected vessels, ranging from coronary artery disease to peripheral artery disease, and critically, increasing the risk of major cardiovascular events. Ultimately, advanced atherosclerosis can lead to serious outcomes such as stroke[9]and other forms of atherosclerotic cardiovascular disease (ASCVD)[7], underscoring its profound impact on overall health.
Cellular and Molecular Mechanisms of Plaque Development
Section titled “Cellular and Molecular Mechanisms of Plaque Development”The initiation and progression of atherosclerotic plaques involve intricate molecular and cellular pathways within the arterial wall. Endothelial dysfunction, often triggered by factors like oxidized low-density lipoproteins (LDL), is a key early event, leading to increased vascular permeability and the expression of adhesion molecules. This allows for the recruitment and infiltration of monocytes, which differentiate into macrophages and internalize modified LDL, transforming into foam cells that contribute significantly to the growing plaque.
Various biomolecules and metabolic processes play critical roles in this cellular cascade. For instance, the CETP gene(Cholesteryl Ester Transfer Protein) has been linked to cardiovascular resilience, suggesting its involvement in lipid metabolism and protection against ASCVD[7]. While the full spectrum of signaling pathways is vast, the process involves intricate regulatory networks governing inflammation, cell proliferation, and lipid handling. Research has also explored less conventional pathways, such as a “taste transduction pathway” that has been suggested to play a role in carotid plaque formation [3], highlighting the diverse molecular mechanisms that can influence arterial health.
Genetic and Epigenetic Influences
Section titled “Genetic and Epigenetic Influences”Genetic factors are significant determinants of an individual’s susceptibility to atherosclerosis, with numerous genetic mechanisms contributing to disease risk. Genome-wide association studies (GWAS) have successfully identified common genetic variants and specific loci associated with subclinical atherosclerosis measures like carotid intima-media thickness and carotid plaque[2], [6], [4], [10]. These genetic insights reveal specific gene functions and regulatory elements that modulate arterial health and disease progression.
Beyond common single nucleotide polymorphisms, specific genetic variants can have more nuanced effects on gene expression patterns and cellular functions. For example, a 3’UTR genetic variant of theRARB gene (Retinoic Acid Receptor Beta) has been associated with carotid intima-media thickness [5], implying that regulatory elements within gene untranslated regions can influence disease development, potentially through epigenetic modifications or altered mRNA stability. Furthermore, protective genetic variation, such as that found in theCETP gene, contributes to cardiovascular resilience, offering insights into mechanisms that confer protection against atherosclerotic cardiovascular disease[7].
Systemic Consequences and Gene-Environment Interactions
Section titled “Systemic Consequences and Gene-Environment Interactions”Atherosclerosis is a systemic condition, with its manifestations in one arterial bed often reflecting disease in others, leading to widespread tissue and organ-level effects. The presence of carotid intima-media thickness and carotid plaque loci is strongly implicated in broader cardiovascular outcomes, emphasizing the interconnectedness of arterial health throughout the body[4]. The progressive nature of atherosclerosis can lead to organ-specific damage, such as coronary heart disease affecting the heart, or contribute to events like stroke when cerebral arteries are compromised[9].
Moreover, the development and severity of atherosclerosis are critically influenced by complex gene-environment interactions. Genetic predispositions can be modulated by external factors, altering an individual’s risk profile. A notable example is thePIGR-FCAMR locus, which has been linked to coronary atherosclerosis through interactions between specific genetic variants and residential exposure to traffic[8]. Such interactions highlight how environmental stressors can amplify or mitigate genetic susceptibilities, leading to homeostatic disruptions and impacting the overall systemic consequences of the disease, including the risk of stroke and other atherosclerotic cardiovascular diseases[9], [7].
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Atherosclerosis, a chronic inflammatory disease of the arterial wall, involves a complex interplay of molecular pathways and regulatory mechanisms that drive its initiation and progression. Genetic predispositions, metabolic dysregulation, and environmental factors converge to disrupt vascular homeostasis, leading to the characteristic plaque formation and arterial stiffening.
Vascular Inflammation and Immune Responses
Section titled “Vascular Inflammation and Immune Responses”Atherosclerosis is fundamentally an inflammatory disease, with its early stages marked by endothelial dysfunction and the recruitment of immune cells[1]. This process is orchestrated by intricate signaling pathways, where receptor activation on endothelial cells and monocytes by stimuli like oxidized lipids initiates intracellular signaling cascades, such as NF-κB pathways. These cascades lead to transcription factor regulation and the subsequent expression of adhesion molecules and chemokines, which are crucial for leukocyte extravasation into the arterial wall. Once inside, leukocytes differentiate into macrophages and foam cells, perpetuating a chronic inflammatory cycle that drives plaque development [1]. Genetic studies reinforce the significance of these immune-mediated pathways, with variants within the PIGR-FCAMR locus linked to coronary atherosclerosis, suggesting a role for immunoglobulins and Fc receptors in modulating inflammatory responses or immune cell trafficking, thereby influencing disease susceptibility and progression[8].
Lipid Metabolism and Endothelial Function
Section titled “Lipid Metabolism and Endothelial Function”Dysregulation of metabolic pathways, particularly lipid metabolism, is a central mechanism in atherosclerosis, directly impacting endothelial function and plaque formation. Aberrant biosynthesis, transport, and catabolism of lipoproteins, especially low-density lipoprotein (LDL) cholesterol, result in its accumulation and oxidation within the arterial wall. Endothelial cells, under metabolic stress, exhibit altered gene regulation and protein modification, which impairs their protective functions and promotes lipid uptake and retention. This metabolic perturbation creates a microenvironment conducive to the initiation and growth of atherosclerotic plaques. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with carotid intima-media thickness (CIMT) and plaque, phenotypes indicative of subclinical atherosclerosis, with many of these loci implicated in lipid processing pathways[2]. These genetic findings highlight critical regulatory mechanisms governing lipid flux and cellular responses to lipid overload, suggesting that variants affecting energy metabolism or lipid storage can significantly influence disease risk, potentially through allosteric control of key metabolic enzymes.
Genetic Regulation of Vascular Structure and Remodeling
Section titled “Genetic Regulation of Vascular Structure and Remodeling”The structural integrity and dynamic remodeling of arterial walls are precisely controlled by intricate regulatory mechanisms, including gene regulation and various post-translational modifications of proteins. These processes are vital for maintaining vascular homeostasis and are frequently dysregulated in atherosclerosis, contributing to arterial stiffening and the development of vulnerable plaques. Intracellular signaling cascades, activated by factors such as mechanical stress or growth factors, can lead to the transcription factor regulation of genes involved in extracellular matrix synthesis and smooth muscle cell proliferation and migration. This complex interplay contributes to the emergent properties of a diseased vessel, such as increased carotid intima-media thickness[2]. Genetic predispositions play a significant role in modulating these structural changes, as GWAS have identified loci associated with subclinical atherosclerosis in various arterial territories, indicating that genetic variants can influence the hierarchical regulation of genes critical for vascular cell function and extracellular matrix organization[6]. Furthermore, an extreme phenotype approach has suggested the involvement of taste transduction pathways in carotid plaque, implying a broader systems-level integration where seemingly unrelated pathways might contribute to vascular remodeling and disease susceptibility through complex network interactions[3].
Integrated Metabolic and Environmental Influences
Section titled “Integrated Metabolic and Environmental Influences”Atherosclerosis arises from a complex interplay of genetic predispositions, metabolic pathways, and environmental factors, showcasing significant systems-level integration. Metabolic regulation, encompassing aspects of energy metabolism and nutrient sensing, is intrinsically linked with inflammatory and structural pathways through extensive pathway crosstalk. For instance, nutrient excess can activate signaling pathways that promote inflammation and alter gene regulation in vascular cells, fostering a pro-atherogenic environment. This intricate network of interactions means that dysregulation in one pathway can have cascading effects across multiple biological systems, leading to a systemic dysregulation that characterizes the disease. Crucially, environmental factors, such as residential exposure to traffic, can interact with specific genetic variants, like those within the PIGR-FCAMR locus, to significantly increase the risk of coronary atherosclerosis[8]. This gene-environment interaction underscores how external stimuli can modulate the expression or activity of genes, leading to an exacerbated disease phenotype. Understanding these network interactions and hierarchical regulation is essential for identifying disease-relevant mechanisms and developing targeted therapeutic strategies that account for both genetic susceptibility and environmental triggers[9].
Clinical Relevance
Section titled “Clinical Relevance”Risk Stratification and Personalized Prevention
Section titled “Risk Stratification and Personalized Prevention”Atherosclerosis involves complex genetic and environmental interactions, making risk stratification crucial for targeted prevention. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with subclinical atherosclerosis measures, such as carotid intima media thickness (CIMT) and plaque presence, which serve as early indicators of disease burden[2] [6]. These genetic insights, combined with environmental factors like residential exposure to traffic, can help identify individuals at higher risk for conditions like coronary atherosclerosis, enabling more personalized prevention strategies[8]. For example, identifying specific genetic variants associated with carotid artery stenosis can inform targeted interventions, potentially guiding decisions on lifestyle modifications or early pharmacological treatments before overt clinical events occur[10].
Further enhancing personalized medicine, research into extreme phenotypes and protective genetic variations, such as those in the CETPgene associated with cardiovascular resilience, helps refine risk models and identify individuals who may benefit most from intensive preventative measures or, conversely, those with inherent protective factors[3] [7]. This approach allows for a shift from a one-size-fits-all model to tailored prevention plans, optimizing resource allocation and patient outcomes by focusing on individuals with the highest genetic predisposition and environmental vulnerability.
Diagnostic Utility and Prognostic Assessment
Section titled “Diagnostic Utility and Prognostic Assessment”The clinical utility of assessing atherosclerosis extends to its diagnostic and prognostic capabilities. Measures of subclinical atherosclerosis, such as CIMT and carotid plaque, are valuable diagnostic tools that reflect the early stages of disease progression and can be monitored over time[2] [6]. Genetic loci associated with these subclinical markers have been shown to colocalize with loci influencing cardiovascular outcomes, underscoring their prognostic value in predicting future cardiovascular events[4].
Understanding an individual’s genetic profile, including variants linked to atherosclerosis progression, can enhance the prediction of long-term outcomes and inform treatment response. For instance, the identification of genetic loci associated with carotid artery stenosis provides prognostic information regarding the likelihood of developing severe disease and subsequent complications[10]. This allows clinicians to better anticipate disease trajectories, adjust monitoring strategies, and select appropriate therapeutic interventions, such as statin therapy, based on an individual’s predicted risk and potential response[10] [7].
Comorbidities and Therapeutic Implications
Section titled “Comorbidities and Therapeutic Implications”Atherosclerosis is a systemic inflammatory disease with significant associations and comorbidities, particularly with various forms of stroke[2]. Genetic studies have identified numerous loci linked to both subclinical atherosclerosis and stroke subtypes, highlighting the shared underlying pathologies and the direct clinical implication of atherosclerosis in cerebrovascular events[9] [12] [4]. This understanding allows for integrated patient care, where managing atherosclerosis can directly mitigate the risk of stroke and other cardiovascular complications.
The insights from genetic research also guide therapeutic selection and monitoring. For example, understanding the genetic predisposition to atherosclerosis, including gene-environment interactions like residential traffic exposure, can inform lifestyle recommendations and pharmacological treatment choices[8]. Furthermore, the identification of protective genetic variations, such as those in CETP, can influence decisions regarding cholesterol-lowering medications by predicting individual response and overall cardiovascular resilience[7]. Such personalized therapeutic approaches aim to optimize treatment efficacy and reduce the burden of atherosclerosis-related morbidities.
Frequently Asked Questions About Atherosclerosis
Section titled “Frequently Asked Questions About Atherosclerosis”These questions address the most important and specific aspects of atherosclerosis based on current genetic research.
1. My parents had artery issues; will I get them too?
Section titled “1. My parents had artery issues; will I get them too?”Yes, there’s a notable genetic component to atherosclerosis. You can inherit predispositions, as specific genetic variants are associated with indicators like carotid intima-media thickness (CIMT) and plaque formation. For instance, a variant of theRARB gene has been linked to CIMT. While genetics increase your susceptibility, it’s not a certainty, and environmental factors also play a crucial role.
2. Does living near busy roads increase my heart risk?
Section titled “2. Does living near busy roads increase my heart risk?”Yes, research suggests there can be a complex interaction between your genes and environmental exposures. Studies have shown that a specific genetic locus, PIGR-FCAMR, is linked to coronary atherosclerosis in individuals with residential exposure to traffic, highlighting how your environment can influence genetic risk.
3. Why do some people never get blocked arteries, even if they aren’t super healthy?
Section titled “3. Why do some people never get blocked arteries, even if they aren’t super healthy?”Some individuals possess protective genetic variations that enhance their cardiovascular resilience. For example, certain variants found in theCETPgene have been identified as influencing this protective effect, helping some people to naturally resist the development of atherosclerosis more effectively.
4. I eat well and exercise, but am I still at risk for artery plaque?
Section titled “4. I eat well and exercise, but am I still at risk for artery plaque?”Yes, even with a healthy lifestyle, your genetic makeup can still influence your susceptibility. Specific genetic variants are associated with key indicators like plaque formation, meaning that while lifestyle is critical, genetic predispositions can still contribute to your individual risk.
5. Can a genetic test tell me if my arteries are likely to get bad?
Section titled “5. Can a genetic test tell me if my arteries are likely to get bad?”Yes, genetic testing, particularly using insights from genome-wide association studies (GWAS), can identify common genetic variants linked to markers of atherosclerosis like carotid intima-media thickness and plaque. This can provide insight into your personal genetic predisposition and potential future risk.
6. Can my sense of taste actually affect my artery health?
Section titled “6. Can my sense of taste actually affect my artery health?”Surprisingly, yes, novel pathways are being explored for their potential role. Research is investigating connections between taste transduction pathways and the development of carotid plaque, suggesting that how you perceive taste might indeed have an unexpected link to your artery health.
7. My sibling has clear arteries, but my doctor says mine are problematic. Why the difference?
Section titled “7. My sibling has clear arteries, but my doctor says mine are problematic. Why the difference?”Even within families, genetic variations and gene-environment interactions can differ significantly. You and your sibling might have inherited different sets of genetic risk factors, or experienced unique environmental exposures, leading to different disease outcomes despite sharing a family history.
8. Can healthy living really overcome my family’s “bad genes” for heart disease?
Section titled “8. Can healthy living really overcome my family’s “bad genes” for heart disease?”While genetics play a significant role, healthy living can absolutely help mitigate your risk. Lifestyle choices strongly interact with your genetic predispositions, and medical management strategies, such as cholesterol-lowering medications like statins, are crucial for slowing disease progression and reducing risks, even with a genetic background.
9. Does my ethnic background change my artery risk profile?
Section titled “9. Does my ethnic background change my artery risk profile?”Yes, genetic risk factors for atherosclerosis can vary across different ancestries. Large-scale multi-ancestry genome-wide association studies are conducted specifically to identify these diverse genetic predispositions and understand their impact across various populations, which can influence your personal risk assessment.
10. Why do I feel fine, but my doctor says my arteries are starting to get bad?
Section titled “10. Why do I feel fine, but my doctor says my arteries are starting to get bad?”Atherosclerosis often progresses silently, with early stages showing no noticeable symptoms. Doctors can detect “hidden signs” like increased carotid intima-media thickness (CIMT) and the presence of arterial plaque through specialized tests, even when you feel perfectly healthy. These subclinical markers are important predictors of future cardiovascular events.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Ross, R. “Atherosclerosis—an inflammatory disease.”N Engl J Med, 1999.
[2] Bis, J. C. et al. “Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.” Nat Genet, 2011, PMID: 21909108.
[3] Dueker, N. D. et al. “Extreme Phenotype Approach Suggests Taste Transduction Pathway for Carotid Plaque in a Multi-Ethnic Cohort.” Stroke, 2020, PMID: 32811377.
[4] Franceschini, N, et al. “GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.”Nat Commun, 2017.
[5] Lopez-Mejias, R, et al. “A genome-wide association study identifies a 3’UTR genetic variant of RARB associated with carotid intima-media thickness in rheumatoid arthritis.”Arthritis Rheumatol, 2018.
[6] O’Donnell, C. J. et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, 2007, PMID: 17903303.
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