Coronary Atherosclerosis
Introduction
Section titled “Introduction”Coronary atherosclerosis is a progressive disease characterized by the buildup of plaque within the arteries that supply blood to the heart. This accumulation, known as atherosclerosis, narrows the arteries and can restrict blood flow, leading to various cardiovascular complications. The extent of coronary atherosclerosis is often assessed by measures such as the number of diseased coronary vessels, reflecting clinically significant atherosclerosis.[1]This condition is a major underlying cause of coronary heart disease (CHD).[2] and shares genetic susceptibilities with other atherosclerotic conditions, such as carotid artery stenosis.[3]
Biological Basis
Section titled “Biological Basis”The development of coronary atherosclerosis has a complex biological basis involving both genetic predispositions and environmental factors. Genome-wide association studies (GWAS) have identified specific genetic loci associated with atherosclerotic diseases. For instance, variants in the_LPA_ gene, such as rs10455872 , are strongly associated with lipoprotein(a) levels and carotid artery atherosclerosis disease (CAAD).[2] These _LPA_variants are also linked to residual cardiovascular risk even in patients receiving statin therapy.[4] Other genetic regions, like the _TYW1_–_AUTS2_ locus (rs6952610 ), have also been implicated in CAAD.[2] Beyond individual genetic variants, gene-environment interactions play a crucial role. Research has shown that the _PIGR_–_FCAMR_locus is linked to coronary atherosclerosis through interactions between genetic variants and residential exposure to traffic.[1] Similarly, a variant rs2822693 located downstream of _SAMSN1_ is associated with the number of diseased coronary vessels in interaction with traffic exposure. _SAMSN1_ is expressed in various tissues, including the heart, and its expression is upregulated in atherosclerotic lesions.[1] Integrating data on open chromatin regions, allele-specific DNA openness, and tissue-specific expression quantitative trait loci (eQTLs) helps identify potential regulatory variants influencing gene expression in these processes.[5]Additionally, an association between coronary atherosclerosis and_COL4A2_ (rs9515203 ) has been observed.[6]
Clinical Relevance
Section titled “Clinical Relevance”Understanding and measuring coronary atherosclerosis is critically important for clinical practice. It allows for the assessment of clinically significant disease, which is essential for diagnosis, prognosis, and guiding treatment decisions.[1] Early identification of individuals at higher genetic risk, particularly those with variants like those in _LPA_ that confer residual risk even with standard treatments, can lead to more personalized and effective preventive strategies.[4]While current measures often focus on clinically significant atherosclerosis, there is also an acknowledgment that subclinical atherosclerosis may be influenced by genetic associations.[1] suggesting a broader scope for future assessment methods.
Social Importance
Section titled “Social Importance”Coronary atherosclerosis represents a significant public health burden globally, contributing substantially to morbidity and mortality from cardiovascular diseases. Research into its genetic and environmental determinants has profound social importance. Identifying genetic predispositions and gene-environment interactions, such as those involving traffic-related air pollution.[1] can inform public health interventions aimed at reducing exposure to harmful environmental factors and developing targeted preventive strategies. Furthermore, understanding how genetic risk varies across different racial and ethnic groups.[2]is crucial for addressing health disparities and ensuring equitable healthcare outcomes. This ongoing research contributes to the broader effort to prevent, manage, and ultimately reduce the societal impact of coronary artery disease.[7]
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The research faced limitations due to restricted sample sizes within race-stratified cohorts, particularly in African ancestry groups, where limited statistical power prevented the detection of significant associations.[2]While some replication was achieved in independent cohorts of different ethnicities drawn from the same source population, this only partially mitigated the issue of sample size.[1] The absence of additional, fully independent replication cohorts remains a primary limitation, meaning current findings require careful interpretation until further validation in diverse populations is performed.[1]The reliance on cohorts derived from cardiac catheterization laboratories, such as the CATHGEN cohort, introduces a potential selection bias, as these individuals are already presenting with clinically significant cardiovascular concerns.[1]This study design might overrepresent individuals with advanced disease, potentially influencing observed effect sizes and limiting the detection of associations relevant to earlier stages of coronary atherosclerosis. Furthermore, the exclusion of certain covariates like BMI, coronary heart disease (CHD), and smoking status from main analyses due to data availability across all sites in some studies could introduce residual confounding, potentially altering observed effect sizes and p-values even when later included in sensitivity analyses.[2]
Phenotypic Definition and Environmental Exposure Assessment
Section titled “Phenotypic Definition and Environmental Exposure Assessment”The chosen measure of coronary atherosclerosis, based on the number of diseased coronary vessels, focuses on clinically significant disease as assessed by a physician.[1]While valuable for clinical relevance, this approach does not capture subclinical atherosclerosis, which may also be influenced by genetic and environmental factors but remains undetected.[1] Consequently, the study might miss associations relevant to the initiation or early progression of the condition.
The assessment of traffic-related air pollution exposure relied on distance from primary residence to the nearest major roadway, a well-validated proxy.[1] However, this method does not allow for the identification of specific traffic air pollution components contributing to the observed associations, nor does it differentiate between traffic-generated pollution and other sources like biomass burning or wood smoke.[1]Refining these associations would necessitate detailed maps of land usage and traffic patterns, which are often unavailable or limited to specific geographic areas, thus restricting the precision of environmental exposure modeling.[1]
Generalizability and Ancestry Diversity
Section titled “Generalizability and Ancestry Diversity”The research was primarily conducted within a single geographic region, raising questions about the generalizability of the findings to other populations where local traffic emissions and genetic backgrounds may differ.[1] Although a trans-ethnic approach was employed, the scope of ancestry groups studied was limited, predominantly focusing on European and African ancestries.[1] Other ancestry subsets were too small for robust subgroup analyses, limiting the ability to observe further ethnicity-driven heterogeneity.[2] The observed ethnicity-driven heterogeneity in associations highlights the importance of expanding research to include a wider range of ethnicities beyond European and African ancestries.[1]This broader validation is crucial to understand the full spectrum of genetic and gene-environment interactions influencing coronary atherosclerosis and to ensure that predictive models and interventions are equitable and effective across diverse global populations.[2]More work on the risk and genetic predictors of coronary atherosclerosis in non-European ancestry groups is warranted to address these knowledge gaps.[2]
Variants
Section titled “Variants”Genetic variants associated with the development and progression of coronary atherosclerosis often exert their influence through diverse mechanisms, ranging from structural integrity of blood vessels to lipid metabolism and immune responses. Several specific single nucleotide variants (SNVs) have been identified, highlighting various pathways involved in this complex disease. These variants can impact gene expression, protein function, or regulatory networks, collectively contributing to an individual’s susceptibility to coronary artery disease and its related phenotypes, such as carotid artery stenosis.
Variants impacting vascular structure and development include rs9515203 within the COL4A2 gene and rs682112 near NAV1. The COL4A2 gene encodes a crucial component of type IV collagen, a primary structural protein found in the basement membranes that support blood vessels. Disruptions in these collagen networks can compromise vascular integrity, influencing the stability of atherosclerotic plaques and the overall risk of myocardial infarction.[6] The rs9515203 variant has been significantly associated with coronary atherosclerosis.[6] suggesting its role in modulating the structural resilience of arterial walls. Similarly, rs682112 is located within an intron of the NAV1 gene, which is expressed at higher levels in the aorta compared to other tissues.[2] While NAV1is traditionally associated with neuronal guidance, its prominent expression in the aorta suggests a potential role in vascular biology, possibly influencing cell migration or endothelial function critical for arterial health and disease. This variant was identified as a lead SNV in a genome-wide association study for carotid artery stenosis.[2] further linking it to arterial atherosclerotic conditions.
Other variants contribute to atherosclerosis by affecting lipid metabolism and immune responses. Thers118039278 variant, located in the LPA gene, is particularly relevant as LPAencodes apolipoprotein(a), a key component of lipoprotein(a) (Lp(a)). Elevated Lp(a) levels are a recognized independent risk factor for coronary heart disease, and variants inLPAare known to influence these levels, thereby modulating cardiovascular risk. ThisLPAvariant has been significantly associated with coronary heart disease.[2]and carotid artery atherosclerotic disease, showing a clear odds ratio for increased risk.[2] Additionally, the FCAMR gene, which encodes an immune receptor, is implicated by variants rs1856746 and rs2791713 . These variants are located in the FCAMR-PIGRlocus and have been found to replicate associations with coronary atherosclerosis through interactions with residential traffic exposure.[1] Both rs1856746 and rs2791713 function as expression quantitative trait loci (eQTLs).[1]indicating they can influence the expression of nearby genes, potentially altering immune cell responses and inflammation within arterial walls, which are central to atherosclerosis development.
Finally, the rs2526620 variant highlights the role of transcriptional regulation and cellular plasticity in atherosclerosis. This intergenic variant is situated between theHDAC9 and TWIST1 genes.[2] HDAC9 (Histone Deacetylase 9) plays a role in chromatin remodeling, affecting gene expression crucial for cell differentiation and proliferation in vascular cells, while TWIST1 is a transcription factor involved in epithelial-mesenchymal transition and cell migration, processes relevant to vascular remodeling. As a lead SNV identified in a genome-wide association study for carotid artery stenosis.[2] rs2526620 likely influences the regulatory landscape of these genes, thereby impacting cellular processes within the arterial wall that contribute to plaque formation and stability.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2526620 | HDAC9 - TWIST1 | coronary atherosclerosis Ischemic stroke |
| rs682112 | IPO9-AS1, NAV1 | coronary atherosclerosis aortic stenosis, aortic valve calcification |
| rs9515203 | COL4A2 | coronary artery disease carotid artery thickness coronary atherosclerosis angina pectoris myocardial infarction |
| rs112043140 | LRRC2 | coronary atherosclerosis coronary artery disease |
| rs2073532 | ETV1 | coronary atherosclerosis |
| rs8003602 | HHIPL1 - CYP46A1 | coronary artery disease coronary atherosclerosis cardiovascular disease |
| rs10841443 | TCP1P3 - LINC02468 | coronary artery disease coronary atherosclerosis myocardial infarction |
| rs2791713 | FCAMR - C1orf116 | coronary atherosclerosis |
| rs118039278 | LPA | peripheral arterial disease ankle brachial index coronary atherosclerosis depressive symptom , low density lipoprotein cholesterol lipoprotein A |
| rs1856746 | FCAMR | coronary atherosclerosis |
Core Definition and Pathophysiology of Coronary Atherosclerosis
Section titled “Core Definition and Pathophysiology of Coronary Atherosclerosis”Coronary atherosclerosis is precisely defined as a progressive disease characterized by the buildup of fatty deposits, known as plaques, within the walls of the coronary arteries. These arteries are vital as they supply blood to the heart muscle. Over time, this accumulation leads to the narrowing and hardening of the arteries, a process that can impede blood flow. The presence and extent of these blockages are crucial indicators of clinically significant coronary atherosclerosis, representing a major underlying cause of various cardiovascular conditions.[1] Understanding this fundamental pathological process is essential for its accurate diagnosis, classification, and management.
Clinical Classification and Severity Assessment
Section titled “Clinical Classification and Severity Assessment”The severity of coronary atherosclerosis is primarily classified through the assessment of the “number of diseased coronary vessels” (NUMDZV), which serves as a key operational definition in clinical practice and research.[1] This variable is annotated by clinicians following catheterization procedures, providing a quantifiable measure of the extent of arterial involvement. A coronary vessel is typically deemed “diseased” if it exhibits a significant blockage greater than 75%.[1]A notable exception and specific criterion applies to the left main coronary artery: if this vessel shows a blockage exceeding 50%, it is clinically considered equivalent to two-vessel disease, thereby incrementing the NUMDZV by two.[1]This system categorizes the disease from 0 to 3 diseased vessels, offering a direct measure of clinically significant atherosclerosis, though it does not encompass subclinical forms of the disease.[1]
Related Clinical Conditions and Diagnostic Context
Section titled “Related Clinical Conditions and Diagnostic Context”Beyond the direct assessment of arterial blockages, the diagnostic and prognostic context of coronary atherosclerosis often incorporates several related clinical conditions and risk factors. Hypertension, hyperlipidemia, and type 2 diabetes are frequently observed comorbidities, and their presence is clinically defined through evidence such as pharmacologic treatment regimens, abnormal clinical chemistry results, or existing medical record entries.[1]Furthermore, broader clinical diagnoses like Coronary Heart Disease (CHD) are intricately linked to coronary atherosclerosis. CHD can be identified using standardized nosological systems, for instance, by the presence of at least two International Classification of Disease (ICD)-9 codes for CHD recorded across patient encounters separated by a minimum of 60 days.[2]These contextual factors, defined through clinical data and standardized coding, provide a comprehensive view of the patient’s cardiovascular health status and the systemic implications of atherosclerosis.
Causes of Coronary Atherosclerosis
Section titled “Causes of Coronary Atherosclerosis”Coronary atherosclerosis, characterized by the accumulation of plaque in the coronary arteries, is a complex condition influenced by a combination of genetic predispositions, environmental exposures, and biological processes throughout life. Understanding these multifactorial causes is crucial for prevention and treatment strategies.
Genetic Predisposition and Inherited Risk
Section titled “Genetic Predisposition and Inherited Risk”Genetic factors play a significant role in an individual’s susceptibility to coronary atherosclerosis. Inherited variants contribute to a polygenic risk, meaning that multiple genes, each with a small effect, collectively influence the likelihood of developing the condition. For instance, specific genetic variants have been identified that directly affect inflammatory pathways or vascular function. Research has linked the_PIGR-FCAMR_locus on chromosome 1 to coronary atherosclerosis, suggesting these genes, involved in inflammatory responses, contribute to disease pathogenesis.[1] Similarly, an interaction involving rs10830090 in the _RARS2_gene, which encodes a mitochondrial arginine t-RNA synthase, highlights the role of mitochondrial function, a process implicated in both air pollution response and cardiovascular disease.[1] An EA-specific interaction in a regulatory region associated with _SAMSN1_, a gene previously linked to vascular disease, further demonstrates how specific genetic profiles can influence risk.[1]
Environmental Exposures and Lifestyle Factors
Section titled “Environmental Exposures and Lifestyle Factors”Environmental elements and lifestyle choices are critical drivers of coronary atherosclerosis. Exposure to traffic-related air pollution, for example, is a widespread environmental risk factor strongly associated with adverse cardiovascular outcomes, including coronary atherosclerosis.[1]The proximity of a primary residence to major roadways serves as a validated proxy for this exposure, indicating a geographic influence on disease risk.[1]Beyond pollution, established lifestyle factors such as smoking and an elevated body mass index (BMI) significantly contribute to the development and progression of atherosclerosis.[1]These environmental and lifestyle elements can initiate or exacerbate the inflammatory and oxidative stress processes that underlie plaque formation in the arteries.
Gene-Environment Interactions
Section titled “Gene-Environment Interactions”The interplay between an individual’s genetic makeup and their environment profoundly influences coronary atherosclerosis risk. Genetic predispositions do not operate in isolation; rather, they can modify the impact of environmental triggers. For example, specific genetic variants can enhance or diminish an individual’s susceptibility to the harmful effects of traffic-related air pollution.[1] A genome-wide interaction study revealed that genetic variants within the _PIGR-FCAMR_ locus can interact with residential exposure to traffic, thereby influencing the number of diseased coronary vessels.[1]Such interactions underscore the importance of considering both inherited risk and environmental exposures together to comprehensively assess an individual’s true risk for developing coronary atherosclerosis.
Developmental, Epigenetic, and Comorbid Influences
Section titled “Developmental, Epigenetic, and Comorbid Influences”Beyond direct genetic inheritance, developmental and epigenetic factors contribute to coronary atherosclerosis by influencing gene expression patterns over a lifetime. Early life experiences and exposures can lead to epigenetic modifications, such as changes in DNA methylation or histone modifications, that alter gene activity without changing the underlying DNA sequence.[1]These modifications, detectable in open chromatin regions or allele-specific DNA openness, can impact transcription factor binding and nucleosome positioning, thereby affecting the expression of genes relevant to cardiovascular health.[1]Furthermore, existing comorbidities significantly exacerbate atherosclerosis. Conditions like hypertension, hyperlipidemia, and type 2 diabetes are well-established risk factors that accelerate arterial damage and plaque accumulation.[1]Age is also a primary contributor, with the risk of coronary atherosclerosis generally increasing with advancing age due to cumulative exposure to risk factors and natural biological changes.
Biological Background
Section titled “Biological Background”Coronary atherosclerosis is a chronic inflammatory disease affecting the arteries that supply blood to the heart. It is characterized by the accumulation of lipids, immune cells, and fibrous tissue within the arterial walls, leading to the formation of plaques. This progressive condition can narrow the arteries, restrict blood flow, and, if plaques rupture, lead to serious cardiovascular events such as heart attacks. The development and progression of coronary atherosclerosis are influenced by a complex interplay of genetic, environmental, and lifestyle factors.
Initiation and Progression of Atherosclerosis: Cellular and Molecular Mechanisms
Section titled “Initiation and Progression of Atherosclerosis: Cellular and Molecular Mechanisms”Atherosclerosis begins with damage or dysfunction of the endothelium, the inner lining of blood vessels, often triggered by risk factors such as high cholesterol, hypertension, and exposure to environmental toxins. This endothelial dysfunction increases the permeability of the vessel wall, allowing low-density lipoproteins (LDL) to infiltrate the arterial intima, where they become oxidized. The presence of oxidized LDL initiates an inflammatory response, attracting monocytes that differentiate into macrophages.[1] These macrophages engulf the oxidized lipids, transforming into foam cells, which are a hallmark of early atherosclerotic lesions.
As the disease progresses, smooth muscle cells migrate from the media into the intima, proliferate, and synthesize extracellular matrix components, forming a fibrous cap over the lipid-rich core of the plaque. This growing plaque can narrow the arterial lumen, impeding blood flow and potentially leading to symptoms like angina.[1] The stability of these plaques is crucial for clinical outcomes; vulnerable plaques with thin fibrous caps are prone to rupture, leading to thrombus formation and acute events like myocardial infarction. Genetic variants, such as those at the COL4A1/COL4A2 locus, can affect vascular cell survival and plaque stability, highlighting the molecular underpinnings of arterial integrity.[8]Moreover, the manifestation of atherosclerosis can differ between vascular beds, with coronary and carotid arteries exhibiting distinct pathophysiological mechanisms and genetic associations, even in the presence of shared risk factors.[2]
Genetic Architecture and Regulatory Networks in Atherosclerosis
Section titled “Genetic Architecture and Regulatory Networks in Atherosclerosis”An individual’s genetic makeup significantly influences susceptibility to coronary atherosclerosis, with specific genes and their regulatory elements playing critical roles in disease development. Genome-wide association studies (GWAS) have identified numerous genetic variants, including single nucleotide polymorphisms (SNPs), associated with atherosclerosis-related phenotypes. Many of these variants reside in non-coding regions of the genome, where they impact gene expression patterns by affecting regulatory elements such as promoters, enhancers, or regions of open chromatin.[1] For instance, the rs2822693 variant, located in an open chromatin region downstream of the SAMSN1gene, has been linked to coronary atherosclerosis and correlates withSAMSN1expression in hematopoietic cells, suggesting a role in immune cell-mediated inflammatory responses critical to the disease.[1] Regulatory networks, involving transcription factors and epigenetic modifications, further fine-tune gene expression in response to various physiological and environmental stimuli, thereby affecting cellular functions essential for vascular health. Research integrating data on open chromatin regions, allele-specific DNA openness, and tissue-specific expression quantitative trait loci (eQTLs) helps to identify variants that regulate gene expression by influencing transcription factor binding or nucleosome positioning.[1] A key example is the COL4A1/COL4A2 locus, where genetic variants influence the expression of these genes, which encode crucial structural components of the vascular basement membrane. Altered COL4A1/COL4A2 expression can impair vascular cell survival and compromise atherosclerotic plaque stability, increasing the risk of myocardial infarction.[8] Furthermore, the PIGR-FCAMRlocus on chromosome 1 has been implicated in coronary atherosclerosis through complex interactions between genetic variants and environmental factors, highlighting the dynamic interplay between inherited predispositions and external exposures.[1]
Metabolic and Systemic Disruptions in Coronary Atherosclerosis
Section titled “Metabolic and Systemic Disruptions in Coronary Atherosclerosis”Coronary atherosclerosis is closely intertwined with systemic metabolic dysregulations that disrupt normal vascular homeostasis. Established clinical risk factors such as hyperlipidemia, hypertension, and type 2 diabetes significantly accelerate the atherosclerotic process.[1]Hyperlipidemia, particularly elevated levels of LDL cholesterol, directly contributes to the initial lipid accumulation within arterial walls, a foundational event in plaque formation. Beyond general cholesterol levels, specific biomolecules like lipoprotein (a) (Lp(a)) are recognized as important contributors to cardiovascular risk, with genetically loweredLp(a)levels demonstrating distinct phenotypic characteristics relevant to cardiovascular health.[9] Race-based differences in Lp(a)-associated atherosclerosis underscore the complex genetic and environmental influences on its pathological impact.[10] These metabolic imbalances foster a chronic inflammatory environment and a pro-thrombotic state within the vasculature, promoting plaque development and progression. The sustained inflammatory response involves various cellular functions and signaling pathways, including the activation of B cells and peripheral blood mononuclear cells, where genes such as SAMSN1 are upregulated in atherosclerotic lesions.[1]This emphasizes the critical role of immune cell activity in the pathogenesis of atherosclerosis. Additionally, mitochondrial function, vital for cellular metabolism and energy production, is implicated in the disease, as evidenced by associations of genetic variants withinRARS2, a mitochondrial arginine tRNA synthetase, with coronary atherosclerosis.[1]These systemic metabolic disruptions collectively contribute to the widespread vascular damage characteristic of coronary atherosclerosis, affecting overall cardiovascular health.
Gene-Environment Interactions in Atherosclerosis Development
Section titled “Gene-Environment Interactions in Atherosclerosis Development”The development and progression of coronary atherosclerosis result from complex interactions between an individual’s genetic makeup and their environmental exposures. Gene-environment interactions are crucial in cardiovascular disease pathogenesis, where genetic susceptibilities can be modulated by external factors.[1]Traffic-related air pollution is a recognized environmental contributor to cardiovascular disease morbidity and mortality, with documented associations with coronary atherosclerosis.[1]Genetic variants can influence how individuals respond to such environmental stressors, thereby affecting their risk of developing the disease. For example, a genome-wide interaction study revealed an association between specific genetic variants in thePIGR-FCAMRlocus and coronary atherosclerosis that is significantly influenced by residential exposure to traffic pollution.[1] These interactions often involve regulatory networks where environmental cues can alter gene expression patterns or modify cellular functions. For instance, the rs2822693 variant, located in an open chromatin region near SAMSN1, shows an association with coronary atherosclerosis that is modulated by traffic exposure.[1] Since SAMSN1 is involved in B cell activation and is upregulated in atherosclerotic lesions, this suggests that environmental pollutants might exacerbate inflammatory pathways in individuals with specific genetic predispositions.[1]The systemic consequences of these gene-environment interactions manifest as varied disease phenotypes and progression rates, underscoring the necessity of integrating both internal genetic factors and external environmental influences to comprehensively understand the complex etiology of coronary atherosclerosis.
Inflammatory Signaling and Immune Cell Activation
Section titled “Inflammatory Signaling and Immune Cell Activation”Coronary atherosclerosis involves complex inflammatory signaling pathways and immune cell activation, which are critical for disease initiation and progression. Genes such asFCAMR and PIGR are implicated as inflammatory response genes, suggesting their role in modulating the immune system’s reaction within the arterial wall.[1]These genes likely participate in receptor activation and subsequent intracellular signaling cascades that lead to the recruitment and activation of immune cells, contributing to the chronic inflammatory state characteristic of atherosclerosis. The dysregulation of these pathways can exacerbate vascular inflammation, promoting the development and instability of atherosclerotic plaques.
Further underscoring the role of immune regulation, the SAMSN1 gene, also known as HACS1, encodes a protein with SAM and SH3 domains, indicating its function as an adaptor or scaffolding molecule in signaling networks.[1] Its expression is notably upregulated in B cell activation signaling cascades, in peripheral blood mononuclear cells, and specifically within atherosclerotic lesions.[1] This suggests that SAMSN1 plays a role in orchestrating immune cell responses that contribute to the inflammatory milieu in diseased vessels, potentially by regulating protein modifications or influencing transcription factor activity to alter gene expression in response to pro-atherogenic stimuli.
Genetic Regulation of Vascular Integrity
Section titled “Genetic Regulation of Vascular Integrity”The integrity and function of vascular structures are tightly controlled by genetic and regulatory mechanisms, with specific loci influencing the susceptibility to coronary atherosclerosis. Genetic variants within theCOL4A1/COL4A2locus, for instance, are associated with coronary heart disease because they affect the expression of theCOL4A1 and COL4A2 genes.[8] These genes encode components of the vascular basement membrane, and their altered expression can impact vascular cell survival, thereby influencing the stability of atherosclerotic plaques and the overall risk of myocardial infarction.[8] Regulatory mechanisms, including gene regulation and post-translational modifications, are pivotal in maintaining vascular health. Genetic variants located in open chromatin regions, which are nucleosome-free sites of DNA, often correlate with the binding of regulatory factors such as transcription factors.[5] These variants can thus regulate gene expression by influencing the accessibility of DNA to transcriptional machinery. For example, a variant identified downstream of SAMSN1 was found in an open chromatin region highly correlated with SAMSN1gene expression in hematopoietic cells, demonstrating how specific genetic changes can modulate local gene activity and contribute to the pathophysiological processes in coronary atherosclerosis.[1]
Metabolic Control and Lipid Homeostasis
Section titled “Metabolic Control and Lipid Homeostasis”Metabolic pathways, particularly those involved in lipid homeostasis, are central to the pathogenesis of coronary atherosclerosis. Variants in theLPAgene are strongly associated with levels of lipoprotein(a) (Lp(a)), a recognized risk factor for coronary disease.[11], [12] Elevated Lp(a) levels reflect dysregulation in lipid metabolism, contributing to the accumulation of lipids within arterial walls and promoting plaque formation. Understanding the genetic control over Lp(a) levels provides insights into metabolic flux control and potential targets for therapeutic intervention aimed at lowering atherogenic lipid profiles.[12]Another gene identified in association with coronary atherosclerosis isRARS2, which encodes a mitochondrial arginyl-tRNA synthetase.[1]While its direct role in atherosclerosis is complex, mitochondrial function is intrinsically linked to cellular energy metabolism, biosynthesis, and catabolism. Dysregulation in mitochondrial pathways can lead to increased oxidative stress and impaired cellular function, both of which are critical factors in endothelial dysfunction and the development of atherosclerotic lesions. Thus, variations affectingRARS2could impact cellular metabolic regulation, contributing to the overall disease pathology.
Gene-Environment Interactions and Systemic Responses
Section titled “Gene-Environment Interactions and Systemic Responses”Coronary atherosclerosis is significantly influenced by the intricate interplay between an individual’s genetic makeup and environmental exposures, representing a critical aspect of systems-level integration. Studies have revealed gene-environment interactions, such as those between genetic variants within theFCAMR-PIGRlocus and residential exposure to traffic-related air pollution, which are linked to coronary atherosclerosis.[1]This demonstrates how environmental stressors can interact with specific genetic predispositions to modulate disease risk, highlighting the importance of considering external factors in the overall pathogenic landscape.
These gene-environment interactions involve pathway crosstalk and network interactions, where environmental signals, like pollutants, activate receptor pathways and intracellular signaling cascades that are influenced by genetic variants.[1]The resultant hierarchical regulation can lead to emergent properties, such as exacerbated inflammatory responses or impaired vascular repair mechanisms, which collectively drive the progression of coronary atherosclerosis. Such complex interactions underscore the need for an integrative approach to identify individuals at higher risk and to develop targeted therapeutic strategies that address both genetic susceptibility and environmental influences.
Assessing Disease Severity and Prognosis
Section titled “Assessing Disease Severity and Prognosis”The of coronary atherosclerosis, often quantified by the number of diseased coronary vessels (NUMDZV) identified during cardiac catheterization, provides crucial diagnostic and prognostic information for patients. This clinician-annotated variable assesses the degree of clinically significant atherosclerosis, specifically blockages greater than 75%, and takes into account the location and dominance of vessels, with severe left main carotid artery disease counting as two-vessel disease.[1]While effective for evaluating significant disease, this measure does not capture subclinical atherosclerosis, which may also be influenced by genetic and environmental factors.[1]Understanding the severity of coronary atherosclerosis through such detailed phenotyping is vital for predicting patient outcomes and informing clinical management. Genetic variants, such as those inCOL4A2 (rs9515203 ), have been associated with coronary atherosclerosis, suggesting a genetic contribution to disease susceptibility and potentially progression.[6]Furthermore, gene-environment interactions, such as those involving traffic-related air pollution exposure, can modulate the risk of coronary atherosclerosis, highlighting the complex interplay of factors that determine disease severity and long-term implications.[1]
Personalized Risk Stratification and Prevention
Section titled “Personalized Risk Stratification and Prevention”Measuring coronary atherosclerosis is fundamental for stratifying individuals into different risk categories, enabling more personalized prevention and treatment strategies. Genetic insights, such as the association ofLPAvariants with carotid artery atherosclerotic disease (CAAD) and coronary heart disease (CHD), contribute to identifying individuals at higher genetic risk.[2] However, the impact of these genetic loci can vary by ancestry, emphasizing the need for diverse population studies to refine risk models and ensure equitable application of personalized medicine approaches.[2]Beyond genetics, incorporating environmental factors alongside clinical and genomic data can further enhance risk stratification. For instance, residential exposure to traffic-related air pollution has been linked to coronary atherosclerosis, and interactions between specific genetic variants and this environmental exposure can modify an individual’s risk.[1]Such comprehensive risk assessment, integrating genetic predispositions, environmental exposures, and detailed clinical measures like NUMDZV, supports targeted prevention strategies and early interventions for high-risk individuals, moving towards a more precise approach to cardiovascular health.
Interplay with Comorbidities and Associated Conditions
Section titled “Interplay with Comorbidities and Associated Conditions”Coronary atherosclerosis rarely exists in isolation and is frequently associated with a spectrum of comorbidities and related cardiovascular conditions, which measurements of its extent can help contextualize. Conditions such as hypertension, hyperlipidemia, and type 2 diabetes are clinically defined factors that often coexist with and contribute to the development and progression of coronary atherosclerosis.[1]These comorbidities are systematically accounted for in studies evaluating coronary atherosclerosis, underscoring their integral role in the disease’s pathophysiology and clinical presentation.[1]While coronary atherosclerosis and carotid artery atherosclerotic disease (CAAD) share common environmental and clinical risk factors, genetic studies suggest distinct pathophysiologic mechanisms between them.[2]For example, some genetic risk loci for ischemic stroke, a consequence of carotid atherosclerosis, may not overlap significantly with those for coronary heart disease.[2]This distinction highlights that while general cardiovascular health markers are important, specific measurements of coronary atherosclerosis are critical for understanding its unique genetic architecture and for managing the complex interplay of systemic and localized atherosclerotic processes.
Frequently Asked Questions About Coronary Atherosclerosis
Section titled “Frequently Asked Questions About Coronary Atherosclerosis”These questions address the most important and specific aspects of coronary atherosclerosis based on current genetic research.
1. My family has heart problems; will I get them too?
Section titled “1. My family has heart problems; will I get them too?”Yes, coronary atherosclerosis has a strong genetic component, so a family history increases your personal risk. Specific genetic variants, like those in the_LPA_gene, are known to be inherited and contribute to plaque buildup in arteries. However, your lifestyle choices also play a crucial role in whether these predispositions manifest.
2. Does living near heavy traffic affect my heart health?
Section titled “2. Does living near heavy traffic affect my heart health?”Yes, research shows your environment can interact with your genes to affect heart health. For instance, specific genetic variants at the _PIGR_–_FCAMR_ locus and near _SAMSN1_have been linked to coronary atherosclerosis when combined with exposure to traffic pollution. This highlights how your daily environment can influence your risk.
3. If I take cholesterol meds, am I safe from heart attacks?
Section titled “3. If I take cholesterol meds, am I safe from heart attacks?”Not necessarily, even with cholesterol-lowering medications like statins, you might still have a “residual risk.” This is because certain genetic variants, particularly in the _LPA_gene, can continue to contribute to cardiovascular risk despite standard treatments. It’s important to discuss all your risk factors with your doctor.
4. Why do some healthy people still get blocked arteries?
Section titled “4. Why do some healthy people still get blocked arteries?”Even if you maintain a healthy lifestyle, genetic predispositions can play a significant role. Some individuals carry specific genetic variants, such as those in the_LPA_ gene or _COL4A2_, that increase their susceptibility to plaque buildup regardless of obvious risk factors. These genetic factors can contribute to atherosclerosis development, even in seemingly healthy individuals.
5. Can a DNA test tell me my heart disease risk?
Section titled “5. Can a DNA test tell me my heart disease risk?”Yes, genetic testing can identify specific variants associated with increased risk for coronary atherosclerosis. For example, knowing if you carry certain variants in the_LPA_ gene could indicate a higher predisposition. This information can help you and your doctor personalize preventive strategies and monitor your heart health more closely.
6. Does my background mean I have different heart risks?
Section titled “6. Does my background mean I have different heart risks?”Yes, genetic risk for coronary atherosclerosis can vary across different racial and ethnic groups. Research is ongoing to understand these differences, but limitations in studying diverse populations mean we don’t always have a complete picture. Recognizing these disparities is important for ensuring equitable healthcare outcomes and tailored prevention strategies.
7. Why might my sibling have heart issues, but I don’t?
Section titled “7. Why might my sibling have heart issues, but I don’t?”Even with shared genetics, individual differences arise from a combination of specific inherited variants and unique environmental exposures. While you share family genes, one sibling might have inherited different protective or risk-increasing variants, or had different exposures to factors like traffic pollution, influencing their personal risk.
8. Can healthy habits overcome my family’s heart history?
Section titled “8. Can healthy habits overcome my family’s heart history?”While genetics significantly influence your predisposition, healthy habits can absolutely help mitigate your risk. Lifestyle choices like diet and exercise can interact with your genetic makeup, potentially reducing the impact of inherited susceptibilities. It’s a balance where both your genes and your daily choices contribute to your overall heart health.
9. Are there heart problems doctors miss until they’re serious?
Section titled “9. Are there heart problems doctors miss until they’re serious?”Yes, current clinical measures often focus on “clinically significant” atherosclerosis, meaning disease that’s already causing noticeable issues. This approach might not capture “subclinical” atherosclerosis, which is plaque buildup that hasn’t yet caused symptoms. Genetic factors can influence these earlier, less obvious stages of the disease.
10. Does my daily environment impact my arteries?
Section titled “10. Does my daily environment impact my arteries?”Your daily environment can indeed interact with your genes to impact your arteries. For example, certain genetic variants can make you more susceptible to coronary atherosclerosis when you’re exposed to factors like traffic-related air pollution. This highlights how your surroundings can influence the genetic predispositions you carry.
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] Ward-Caviness, C. K., et al. “A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic.”PLoS One, 2017.
[2] Palmer, M. R., et al. “Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.” Genet Epidemiol, vol. 45, no. 1, 2021, pp. 4-15.
[3] Dichgans, M., et al. “Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common genetic variants.”Stroke, vol. 45, no. 1, 2014, pp. 21–28.
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