Carotid Atherosclerosis
Introduction
Section titled “Introduction”Carotid atherosclerosis is a chronic disease characterized by the accumulation of lipid-rich and inflammatory deposits, known as plaques, within the sub-intimal space of medium and large arteries, particularly those supplying blood to the brain through the neck.[1] This process leads to the thickening of arterial walls and a reduction in the arterial lumen, potentially impeding blood flow.[2]As atherosclerosis often has a long preclinical phase, non-invasive methods like B-mode ultrasound are vital for early detection. These methods measure the common carotid artery intima-media thickness (cIMT) and identify carotid plaques, which are defined by atherosclerotic thickening or luminal narrowing of the carotid artery wall.[1] The cIMT is a measure of the thickness of the inner two layers of the carotid artery wall, typically assessed in segments including the common carotid artery, carotid bifurcation, and internal carotid artery.[3]
Biological Basis
Section titled “Biological Basis”At a biological level, the enlargement of atherosclerotic plaques can restrict blood flow, leading to organ ischemia and tissue necrosis.[1]A critical event is plaque rupture, which can cause abrupt vascular occlusion, triggering severe cardiovascular events.[1]Genetic predisposition plays a significant role in the risk of atherosclerosis.[1]Studies have estimated the heritability of carotid plaque area to be around 69.1% (adjusted for sex and age) and carotid plaque prevalence at 50% (adjusted for various cardiovascular risk factors) in family studies.[2] Similar heritability estimates have been found in studies using unrelated samples, ranging from 49.7% to 70.5% depending on adjustments for risk factors.[2] Genome-wide association studies (GWAS) have identified numerous genetic loci associated with cIMT and carotid plaque.[4] These genetic variants are often located in or near genes involved in cellular signaling, lipid metabolism, and blood pressure regulation.[4] For instance, genes associated with carotid plaque are enriched in terms related to fibroblast activity.[1] Specific candidate genes have been implicated, such as IL5 in men for carotid plaque burden, and FPR1, ABCC1 (associated in women), and PSTPIP2(associated in men) as potential contributors to atherosclerosis pathogenesis and progression, although further validation is needed.[2] Some genetic variations, like rs10263213 , have shown associations with multiple measures of subclinical atherosclerosis, including carotid bulb wall thickness.[5]Research also suggests sex-specific genetic influences, with genetic factors potentially having a stronger impact on atherosclerosis in women, while non-genetic factors like BMI might be more relevant in men.[2]
Clinical Relevance
Section titled “Clinical Relevance”Carotid atherosclerosis is a major clinical concern due to its strong association with cardiovascular outcomes. Plaque rupture and subsequent vascular occlusion can lead to life-threatening events such as myocardial infarction and ischemic stroke.[1]Early detection of subclinical atherosclerosis, through measures like cIMT and carotid plaque presence, is crucial for identifying individuals at high risk for future clinical events.[1] Studies indicate that carotid plaque measures are more strongly reflective of atherosclerotic clinical events compared to cIMT.[1]Both cIMT and carotid plaque show significant positive genetic correlations with Coronary Heart Disease (CHD) and stroke.[1] The genetic correlation with CHD has been observed to be twice as strong for carotid plaque (0.52) as for cIMT (0.20).[1]Furthermore, genetic correlations have been identified between cIMT and various stroke subtypes, including ischemic stroke.[1]Many genetic loci associated with cIMT and carotid plaque are also linked to Coronary Artery Disease (CAD), with shared genetic risk loci, such as the 9p21 locus, highlighting the interconnectedness of these conditions.[4]
Social Importance
Section titled “Social Importance”The societal impact of carotid atherosclerosis is substantial, primarily due to its role as a precursor to cardiovascular diseases. Coronary heart disease accounts for a significant portion of deaths, and stroke is also a leading cause of mortality.[1]Given the long preclinical phase of atherosclerosis, early detection and a deeper understanding of its genetic basis offer critical opportunities for prevention.[1]Identifying genetic pathways involved in subclinical atherosclerosis can provide new insights for developing targeted prevention strategies, ultimately reducing the burden of cardiovascular morbidity and mortality on public health.[4]
Phenotypic Heterogeneity and Measurement Challenges
Section titled “Phenotypic Heterogeneity and Measurement Challenges”The assessment of carotid atherosclerosis often involves a single, cross-sectional measure of carotid intima-media thickness (cIMT) and plaque presence, with varying ultrasound protocols and definitions across studies.[4] This heterogeneity in measurement techniques, such as defining plaque as “any plaque” versus “stenosis greater than 25%”, can compromise the ability to consistently detect small genetic associations and integrate findings across different research efforts.[4] Furthermore, specific carotid measures, like internal cIMT, are not consistently available across all cohorts, and maximum cIMT values may be more prone to sampling error, adding complexity to the standardization and interpretation of results.[4] These variations highlight the challenge in precisely phenotyping the trait, which can obscure true genetic signals or limit the comparability of findings.
Generalizability and Statistical Power Limitations
Section titled “Generalizability and Statistical Power Limitations”Many large-scale genetic studies on carotid atherosclerosis have primarily focused on populations of European ancestry.[4] While this approach helps minimize population stratification within these cohorts, it significantly limits the generalizability of findings to other ethnic groups and may overlook ancestry-specific genetic variants or effect sizes.[6] Studies in non-European populations, such as those of African ancestry, have often been underpowered, leading to a lack of significant associations in these groups.[7]Moreover, the availability of high-resolution imaging data, like CCTA, is scarce, which restricts the ability to combine cohorts for increased statistical power in specific types of atherosclerosis assessments.[8] This demographic and methodological imbalance underscores the need for more diverse and larger cohorts to ensure broader applicability of genetic discoveries.
Complex Etiology and Remaining Knowledge Gaps
Section titled “Complex Etiology and Remaining Knowledge Gaps”Understanding the full genetic architecture of carotid atherosclerosis is further complicated by the trait’s multifaceted nature and the influence of various factors. There are indications that the genetics governing the onset of atherosclerosis may differ from those influencing its progression or severity, suggesting that a single genetic model might not capture the full disease trajectory.[2]Furthermore, translating genetic associations from genome-wide association studies (GWAS) into biological understanding is challenging due to limited access to relevant RNA expression data from disease-affected tissues, hindering the identification of causal genes and mechanisms.[1] Advanced analytical methods, such as transcriptome-wide association studies (TWAS), also have inherent methodological limitations based on the prediction of genetically-regulated components, which can impact the accuracy of inferring gene function.[6]The interplay between genetic predispositions and environmental factors, including lifestyle and comorbid conditions like type 2 diabetes, further contributes to the “missing heritability” and the ongoing effort to fully elucidate the complex etiology of carotid atherosclerosis.[2]
Variants
Section titled “Variants”The genetic landscape of carotid atherosclerosis involves a complex interplay of numerous variants and their associated genes, impacting diverse biological pathways that contribute to plaque formation and arterial wall thickening. These variants, identified through large-scale genomic studies, offer insights into the molecular mechanisms underlying cardiovascular risk.
The 9p21 locus, containing the long non-coding RNA CDKN2B-AS1, is a critical region strongly implicated in cardiovascular disease. The variantrs9632884 within or near CDKN2B-AS1 is thought to influence the expression of genes involved in cell cycle regulation and cellular senescence, processes that contribute to the development and progression of atherosclerotic plaques. Studies have shown associations between variants near CDKN2B-AS1at 9p21 with coronary artery calcification (CAC).[9] Another variant, rs4977575 in CDKN2B, also located in this region, has been associated with segment involvement score, an indicator of coronary atherosclerosis burden.[8] These findings suggest that genetic variations in this region, including rs9632884 , play a role in the cellular pathology underlying carotid atherosclerosis. Another significant locus involves the geneEDNRA (Endothelin Receptor Type A), with the variant rs11413744 being a key associated SNP. EDNRAencodes a receptor for endothelin-1, a powerful vasoconstrictor that also promotes cell proliferation and inflammation, all crucial factors in the development of atherosclerosis. TheEDNRA locus has been directly associated with carotid plaque in meta-analyses.[6]Furthermore, this locus shows significant associations with coronary artery disease and all three carotid phenotypes (carotid intima-media thickness and carotid plaque).[4] The consistent association of EDNRAvariants with both subclinical carotid disease and clinically apparent coronary heart disease suggests a shared underlying biological mechanism for these conditions.[4] Variants influencing CCDC71L (Coiled-Coil Domain Containing 71 Like), such as rs17477177 , have been linked to subclinical atherosclerosis. Although the precise function ofCCDC71L remains largely unknown.[1] colocalization analyses have identified its association with carotid intima-media thickness (cIMT) and carotid plaque through tissue-specific expression quantitative trait loci (eQTLs).[1] There is suggestive evidence that variants in CCDC71Lare shared with large vessel disease stroke, highlighting its potential role in broader cerebrovascular health.[1] The gene CFDP1 (Craniofacial Development Protein 1) and its associated variant rs113309773 also contribute to the genetic landscape of carotid atherosclerosis.CFDP1 is part of a known locus, CFDP1-TMEM170A, that has been previously associated with carotid plaque.[1] The variant rs113309773 specifically shows an association with CFDP1, suggesting it may influence the gene’s activity or expression, thereby impacting pathways relevant to vascular health and plaque formation.[1] While CFDP1is broadly involved in development, its specific mechanisms in arterial wall remodeling and atherosclerosis are an area of ongoing investigation.
The variant rs200495339 is located within SMARCA4 (SWI/SNF Related, Matrix Associated Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4), a gene encoding a crucial component of the SWI/SNF chromatin remodeling complex. This complex plays a fundamental role in regulating gene expression by altering chromatin structure, impacting cellular processes like cell growth, differentiation, and DNA repair..[1]In the context of atherosclerosis, dysregulation of chromatin remodeling can influence the inflammatory response, endothelial cell function, and vascular smooth muscle cell phenotype, thereby contributing to plaque initiation and progression. Therefore,rs200495339 may affect SMARCA4 activity, leading to altered gene expression patterns that promote vascular dysfunction and plaque development..[6] Similarly, rs9727451 is associated with FMN2(Formin 2), a gene critical for organizing the actin cytoskeleton within cells. The actin cytoskeleton is essential for various cellular functions, including cell migration, adhesion, and maintaining cell shape, all of which are vital for the integrity and function of endothelial cells lining blood vessels and the behavior of vascular smooth muscle cells..[5] Alterations in these cellular processes due to variants like rs9727451 could impair vascular repair mechanisms, promote inflammatory cell infiltration, or contribute to changes in vascular smooth muscle cell phenotype, thereby playing a role in the development and progression of carotid atherosclerosis..[9]Further genetic insights into carotid atherosclerosis come from variants likers12683261 , associated with LINGO2(Leucine Rich Repeat And Ig Domain Containing 2), andrs4779614 , linked to the TMCO5B - RYR3-DT region. While LINGO2 is primarily known for its role in neuronal development, genes can exert pleiotropic effects across different tissues..[5] Variations in TMCO5B or the lncRNA RYR3-DTcould potentially impact cellular calcium signaling or membrane protein function, processes relevant to vascular cell health and signaling pathways involved in atherosclerosis..[9] Additionally, rs259140 in STEAP2-AS1 and rs2611206 in the NOL8P1 - LINC01179region represent genetic variations that may influence carotid atherosclerosis through less direct or currently uncharacterized mechanisms. BothSTEAP2-AS1 and LINC01179 are long non-coding RNAs, which are known to play crucial regulatory roles in gene expression, affecting cell proliferation, differentiation, and inflammatory responses—all processes integral to the development of atherosclerotic plaques..[1] Pseudogenes like NOL8P1can also have regulatory functions, influencing the expression of their protein-coding counterparts or acting as RNA sponges. Therefore, these variants may alter lncRNA function or expression, subtly influencing the complex cellular environment within the arterial wall and contributing to the risk of carotid atherosclerosis..[6]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs9632884 | CDKN2B-AS1 | carotid atherosclerosis |
| rs17477177 | CCDC71L - LINC02577 | pulse pressure measurement systolic blood pressure smoking status measurement, systolic blood pressure carotid atherosclerosis carotid artery thickness |
| rs113309773 | CFDP1 | carotid atherosclerosis |
| rs12683261 | LINGO2 | carotid atherosclerosis |
| rs11413744 | PRMT5P1 - EDNRA | carotid atherosclerosis peripheral arterial disease |
| rs200495339 | SMARCA4 | carotid atherosclerosis Sphingomyelin (d18:1/17:0, d17:1/18:0, d19:1/16:0) measurement level of Sphingomyelin (d34:2) in blood serum |
| rs4779614 | TMCO5B - RYR3-DT | carotid atherosclerosis |
| rs259140 | STEAP2-AS1 | carotid atherosclerosis |
| rs9727451 | FMN2 | carotid atherosclerosis |
| rs2611206 | NOL8P1 - LINC01179 | carotid atherosclerosis cup-to-disc ratio measurement |
Definition and Pathophysiology of Carotid Atherosclerosis
Section titled “Definition and Pathophysiology of Carotid Atherosclerosis”Carotid atherosclerosis is a chronic, progressive disease characterized by the thickening of the arterial wall and the development of lipid-rich, inflammatory deposits known as plaques within the sub-intimal space of the carotid arteries.[2] This process leads to a reduction in the arterial lumen, which can limit blood flow and result in organ ischemia or tissue necrosis.[1] The underlying pathophysiological mechanism involves a long preclinical phase that can span decades before the onset of clinical symptoms, making early detection critical.[2]The most severe clinical manifestations of carotid atherosclerosis arise from plaque enlargement or rupture, which can cause abrupt vascular occlusion, leading to major cardiovascular events such as myocardial infarction and ischemic stroke.[1]Given its significant contribution to cardiovascular morbidity and mortality, early detection of carotid atherosclerosis is crucial for risk stratification and identifying individuals at high risk for these adverse outcomes, allowing for timely preventative interventions.[6]Major risk factors contributing to its development include high cholesterol, age, sex, smoking, and obesity.[2]
Diagnostic Markers and Measurement Approaches
Section titled “Diagnostic Markers and Measurement Approaches”The assessment of carotid atherosclerosis predominantly relies on non-invasive imaging techniques, particularly B-mode ultrasound, which measures key indicators like carotid intima-media thickness (cIMT) and the presence or size of carotid plaques.[2]Carotid IMT represents the combined thickness of the intimal and medial layers of the carotid artery wall, with increased cIMT being a widely accepted index of subclinical atherosclerosis severity and an indicator of higher cardiovascular risk.[6] Measurements are typically performed on the common carotid artery, outside areas where distinct plaques are present, and can involve parameters such as IMTmax (average of maximum cIMT values) and IMTmean (average of mean cIMT values).[3] Carotid plaque, distinct from generalized cIMT, is defined as atherosclerotic thickening of the artery wall or a measure of luminal narrowing, and is specifically indicative of discrete atherosclerotic lesions.[4] Standardized protocols, such as those recommended by the Mannheim carotid intima-media thickness consensus, are employed for both scanning and reading carotid ultrasound images to ensure consistency and precision in measuring cIMT and characterizing plaques.[3] Automated computerized edge tracking software can further enhance the precision and reduce variance of these measurements, which are crucial for both clinical diagnosis and research applications.[3]
Classification and Clinical Relevance
Section titled “Classification and Clinical Relevance”Carotid atherosclerosis can be classified based on various criteria, including the presence, extent, and severity of plaque or luminal narrowing. For instance, carotid plaques with a thickness of 1.5 mm or greater are categorized as absent, unilateral, or bilateral, providing a simple gradation of disease burden using 2-dimensional grayscale ultrasound images.[8] Carotid artery stenosis, a more advanced stage, is typically defined by the percentage of luminal narrowing, with controls often showing minimal stenosis (e.g., 0%–15%).[7]Diagnostic criteria for carotid artery atherosclerotic disease (CAAD) can involve specific medical codes such as ICD-9 433.1, or procedural codes like CPT 35301 for endarterectomy, indicating significant disease requiring intervention.[7]While both cIMT and carotid plaque are markers of subclinical atherosclerosis, studies suggest that carotid plaque may be a stronger predictor of future cardiovascular events compared to common cIMT alone, although they are correlated.[4]These measures are critical for identifying individuals at high risk for conditions like myocardial infarction, coronary artery disease, and ischemic stroke, with guidelines from organizations like the American Heart Association and the American Society of Echocardiography recognizing their utility in cardiovascular risk assessment.[4]Genetic predisposition also contributes to the risk and manifestation of carotid atherosclerosis; for example, specific loci like9p21are shared genetic risk factors for both carotid plaques and coronary artery disease, while genes such asLEKR1 and GALNT10 modulate sex-differences in cIMT.[3] Other genetic variants, including those in ZHX2, APOC1, and PINX1, have been associated with cIMT, and RCBTB1 is identified as a modifier for the effect of smoking on cIMT.[10]
Subclinical Detection and Non-Invasive Assessment
Section titled “Subclinical Detection and Non-Invasive Assessment”Carotid atherosclerosis often progresses through a prolonged preclinical phase, existing for decades without presenting overt symptoms.[1] During this subclinical stage, the condition is characterized by the gradual accumulation of lipid-rich and inflammatory plaques within the sub-intimal space of medium and large arteries, leading to a measurable thickening of the arterial wall.[1]Non-invasive imaging techniques, predominantly B-mode ultrasound, are instrumental for the early detection and risk stratification of individuals who may be susceptible to future atherosclerotic cardiovascular events, such as myocardial infarction and ischemic stroke.[1]These diagnostic approaches offer a critical window for implementing preventive interventions by identifying at-risk individuals before the onset of symptomatic disease.[1]Objective measures obtained through carotid ultrasound are crucial for assessing subclinical carotid atherosclerosis, including carotid intima-media thickness (cIMT) and the presence or extent of carotid plaques.[1] cIMT is typically defined as the mean of the maximum common carotid artery measurements, taken from either the far or near wall, often averaged from multiple sites across both the left and right arteries.[1] These measurements are typically performed in areas free of visible plaque and benefit from automated computerized edge tracking software to enhance precision and reduce measurement variance.[3] Carotid plaque is identified as a focal wall thickening exceeding 50% of the surrounding wall thickness or as atherosclerotic thickening of the carotid artery wall.[10] Quantitative assessment of plaque burden can involve calculating the total carotid plaque area (CPB) by summing the areas of all detected plaques within an individual.[10]
Clinical Manifestations and Cardiovascular Outcomes
Section titled “Clinical Manifestations and Cardiovascular Outcomes”While carotid atherosclerosis often remains asymptomatic for many years, its progression can lead to severe clinical manifestations, primarily driven by plaque enlargement causing blood flow limitation, organ ischemia, or tissue necrosis.[1]The most critical symptomatic presentations are associated with abrupt vascular occlusion, frequently resulting from plaque rupture, which is the fundamental pathophysiological mechanism underlying major cardiovascular events such as ischemic stroke and myocardial infarction.[1]These acute events are leading causes of mortality and disability worldwide, emphasizing the significance of understanding the transition from subclinical disease to acute clinical syndromes.[6] Clinically apparent carotid artery stenosis (CAAD) represents a more advanced stage where the narrowing of the arterial lumen becomes sufficiently severe to cause symptoms or necessitate medical intervention.[7] Such cases may be identified through diagnostic codes that indicate procedures like endarterectomy or through repeated diagnoses of CAAD over time.[7]Both cIMT and carotid plaque have demonstrated positive and significant genetic correlations with coronary heart disease (CHD) and ischemic stroke, with carotid plaque exhibiting a particularly stronger genetic correlation (0.52 for CHD) compared to cIMT (0.20 for CHD).[1]This highlights their diagnostic and prognostic importance as indicators of an individual’s future cardiovascular risk.[1]
Variability in Presentation and Diagnostic Significance
Section titled “Variability in Presentation and Diagnostic Significance”The presentation and progression of carotid atherosclerosis demonstrate considerable variability across individuals, influenced by a spectrum of factors including age, sex, and established cardiovascular risk factors such as high cholesterol, smoking status, obesity, hypertension, and type 2 diabetes.[2] Age is a prominent risk factor, with studies indicating a wide mean age range for participants undergoing carotid measurements.[4] Sex differences are also apparent, with specific genetic variants, such as those in LEKR1 and GALNT10, known to modulate cIMT, and the gene IL5 potentially influencing carotid plaque burden specifically in men.[3]These inter-individual and demographic variations necessitate the consideration of age- and sex-specific adjustments when assessing subclinical atherosclerosis measures.[5]From a diagnostic standpoint, the early detection of subclinical atherosclerosis through the assessment of cIMT and carotid plaque serves as a valuable tool for risk stratification, even prior to the development of symptoms.[6]While both cIMT and carotid plaque are recognized indicators of atherosclerosis severity, research suggests that the presence and extent of carotid plaque may offer a more robust prediction of future cardiovascular disease risk compared to common cIMT.[4]These objective measures provide crucial prognostic information, aiding clinicians in identifying individuals who could benefit most from intensive preventive strategies to mitigate their risk of subsequent cardiovascular events.[1]
Causes
Section titled “Causes”Carotid atherosclerosis, characterized by the thickening of the carotid artery intima-media and the formation of atherosclerotic plaques, is a complex condition influenced by a combination of genetic, environmental, and lifestyle factors. These elements interact to drive the initiation and progression of vascular damage.
Genetic Susceptibility and Molecular Pathways
Section titled “Genetic Susceptibility and Molecular Pathways”Carotid atherosclerosis, evident as carotid intima-media thickness (cIMT) and carotid plaque, demonstrates a significant heritable component. Family and twin studies consistently show moderate to high heritability for cIMT, ranging from 30% to 60%, and for carotid plaque burden, with estimates between 50% and 70.5% after adjusting for various cardiovascular risk factors.[11] This substantial genetic influence underscores the role of inherited variations in an individual’s predisposition to the condition, although single genetic variants identified through genome-wide association studies (GWAS) often explain only a small fraction of the total phenotypic variation.[12]Numerous genetic loci have been identified as contributing to carotid atherosclerosis, impacting diverse biological pathways. GWAS have pinpointed novel susceptibility loci for both cIMT and carotid plaque, including genes such asPINX1, ADAMTS9, LOXL4, CCDC71L, PRKAR2B, and KIAA1462.[13]These genes are implicated in critical processes like cellular signaling, lipid metabolism, and blood pressure regulation. For example, genes associated with cIMT are often enriched in pathways related to lipoprotein metabolism and cholesterol efflux, while those linked to carotid plaque show enrichment in terms associated with fibroblast proliferation.[14] Specific candidate genes like FPR1(involved in neutrophil activation and inflammation),ABCC1 (cholesterol homeostasis and vascular inflammation), and PSTPIP2(differentially expressed in atherosclerosis) have also been highlighted.[15]Furthermore, established cardiovascular disease risk loci, includingCDKN2B-AS1, LPA-PLG, and APOE, are associated with both coronary and carotid atherosclerosis, often mediating their effects through risk factors such as circulating lipids, diabetes, and obesity.[16] The genetic architecture can be intricate, with different segments of the carotid artery potentially regulated by distinct sets of susceptibility genes.[17]
Environmental and Lifestyle Risk Factors
Section titled “Environmental and Lifestyle Risk Factors”Environmental and lifestyle factors are significant contributors to the development and progression of carotid atherosclerosis. Key traditional risk factors include increasing age, male sex, elevated body mass index (BMI), hypertension (diagnosed by high blood pressure or specific treatment), and type 2 diabetes.[17] Smoking, both active and former, is a particularly potent environmental trigger that substantially increases an individual’s risk.[12] These factors collectively promote a cascade of pathological events, including chronic inflammation, endothelial dysfunction, and the accumulation of lipids within the arterial walls, which are fundamental to the formation of atherosclerotic plaques.
Dietary habits and their subsequent impact on metabolic profiles play a crucial role in vascular health. High levels of total cholesterol and low-density lipoprotein cholesterol (LDLC), often influenced by dietary choices, are strongly correlated with a greater carotid plaque burden, while high-density lipoprotein cholesterol (HDLC) may exert a protective effect.[16]Beyond specific lipid levels, conditions such as obesity and diabetes, which are frequently linked to lifestyle, act as significant mediators of atherosclerosis risk.[16] While traditional risk factors explain a portion of the variance in cIMT, a substantial proportion remains unexplained, suggesting the involvement of additional environmental and genetic influences.[17]
Gene-Environment Interactions and Sex-Specific Effects
Section titled “Gene-Environment Interactions and Sex-Specific Effects”The etiology of carotid atherosclerosis is not solely dictated by genetic predisposition or environmental exposure alone, but rather emerges from intricate interactions between these two domains. Genetic variants can significantly modify the impact of environmental risk factors, which helps explain the observed individual variability in the extent of vascular damage resulting from exposures like cigarette smoking.[12] For instance, the RCBTB1 gene has been identified as a modifier that influences the effect of smoking on cIMT, suggesting that specific genetic backgrounds can either amplify or diminish an individual’s vascular response to tobacco exposure.[12] Such gene-environment interactions are critical for uncovering genes that might otherwise be overlooked in traditional genome-wide association studies.
Carotid atherosclerosis also exhibits notable sex-specific genetic and environmental influences. Studies have demonstrated considerable variability in cIMT between sexes, even after adjusting for conventional risk factors.[17]While some research indicates that genetic influences on atherosclerosis may be more pronounced in women, with polygenic scores for coronary artery disease showing a primary association in females, non-genetic factors such as BMI appear to hold greater relevance for men.[15] Furthermore, specific genetic variants in genes like LEKR1 and GALNT10have been found to modulate these sex differences in cIMT, underscoring the importance of considering sex as a biological variable in understanding the underlying causes of the disease.[17]
Comorbidities and Systemic Influences
Section titled “Comorbidities and Systemic Influences”Carotid atherosclerosis is frequently comorbid with other systemic health conditions, which can both contribute to its development and share common underlying pathophysiological mechanisms. Hypertension and type 2 diabetes are well-established comorbidities that independently and synergistically accelerate atherosclerotic processes.[16]These conditions foster chronic inflammation, oxidative stress, and endothelial dysfunction, all of which are crucial in the formation and progression of plaques within the carotid arteries. Moreover, there are significant genetic correlations between carotid atherosclerosis and major cardiovascular outcomes such as coronary heart disease (CHD) and ischemic stroke, highlighting its role as an indicator of broader systemic cardiovascular risk.[13]Advancing age is a primary non-modifiable risk factor for carotid atherosclerosis. Over an individual’s lifespan, the cumulative exposure to various risk factors, combined with intrinsic age-related changes in vascular biology, contributes to the progressive thickening of the intima-media and the eventual formation of atherosclerotic plaques.[15]While statin treatment serves primarily as a management strategy, its role in modulating lipid profiles and inflammation is critical in mitigating the progression of atherosclerosis.[15]Furthermore, the genetic underpinnings of carotid atherosclerosis can overlap with those of other vascular conditions, such as vascular calcification, where genes likeBMP1 have been implicated.[16]Although coronary and carotid atherosclerosis share many risk factors and pathophysiological similarities, there are also considerable differences in their genetic backgrounds, suggesting distinct yet overlapping systemic influences.[16]
Biological Background
Section titled “Biological Background”Carotid atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-rich and inflammatory deposits, known as plaques, within the sub-intimal space of the carotid arteries.[4] This process leads to the progressive thickening of the arterial wall and reduction of the arterial lumen.[2]The severity of subclinical atherosclerosis can be assessed by measuring carotid intima-media thickness (cIMT) and the presence of carotid plaques using non-invasive ultrasound techniques.[1]These early detections are crucial for risk stratification and identifying individuals at high risk of atherosclerotic cardiovascular diseases.[6]
Pathophysiology and Clinical Manifestations
Section titled “Pathophysiology and Clinical Manifestations”The long preclinical phase of atherosclerosis can span decades before the clinical presentation of symptoms.[6] Plaque enlargement restricts blood flow, potentially causing organ ischemia and tissue necrosis.[1]The most severe clinical outcomes occur when a plaque ruptures, leading to abrupt vascular occlusion and major cardiovascular events such as myocardial infarction and ischemic stroke, which are leading causes of mortality and disability.[1] While both cIMT and carotid plaque reflect vascular pathophysiological processes, carotid plaque burden is more strongly correlated with the risk of atherosclerotic clinical events than cIMT.[1]Major traditional risk factors for atherosclerosis include high cholesterol, age, sex, smoking, and obesity.[2]
Cellular and Molecular Mechanisms of Plaque Development
Section titled “Cellular and Molecular Mechanisms of Plaque Development”The initiation and progression of carotid atherosclerosis involve complex cellular and molecular pathways, including signaling pathways, metabolic processes, and disruptions in cellular functions.[4]Key biomolecules such as lipids, enzymes, and receptors play critical roles. For instance, gene enrichment analyses for cIMT highlight lipoprotein-related terms and cholesterol efflux, indicating the importance of lipid metabolism in its pathogenesis.[1] In contrast, genes associated with carotid plaque are enriched in terms related to fibroblast activity, suggesting distinct cellular contributions to plaque formation.[1]Inflammatory responses are central to atherosclerosis, with circulating and intraplaque neutrophils producing inflammatory mediators likeIL-8, VEGF, and Elastase.[18]Cellular signaling pathways, such as those involving bone morphogenetic protein receptor type IB (BMPR1B), are implicated in processes like vascular calcification.[19] Furthermore, the PRKAR2Bgene, which encodes a regulatory subunit of cAMP-dependent protein kinase, is involved in cAMP-dependent pathways that can lead to adenosine-induced apoptosis of arterial smooth muscle cells.[1] ABC transport proteins, such as ABCC1, are also crucial in cholesterol homeostasis and vascular inflammation.[2] The gene KIAA1462shows suggestive evidence of colocalization with carotid plaque and coronary heart disease, indicating its potential role in these vascular processes.[1]
Genetic and Epigenetic Influences
Section titled “Genetic and Epigenetic Influences”Carotid atherosclerosis has a significant genetic component, with studies estimating a moderate heritability for cIMT, ranging from 0.30 to 0.60, and for carotid plaque burden, up to 70.5% after adjusting for risk factors.[3] Genome-wide association studies (GWAS) have identified numerous genetic loci associated with cIMT and carotid plaque, often mapping to genes involved in cellular signaling, lipid metabolism, and blood pressure homeostasis.[4] Examples include loci near ZHX2, APOC1, and PINX1 for cIMT.[1]While some genetic risk loci are shared between carotid atherosclerosis and coronary artery disease, such as the 9p21 locus, distinct genetic influences are also observed for different carotid artery phenotypes.[7] Genetic mechanisms extend beyond individual gene variants to include regulatory elements and gene expression patterns. For instance, genes like LEKR1 and GALNT10 are known to modulate sex-specific differences in cIMT, highlighting the role of gene-sex interactions.[3] Epigenetic modifications and regulatory networks also contribute, with studies exploring chromatin states, transcription factor binding, and enhancer activity to identify functional roles of genetic variants.[1] The gene RCBTB1 has been identified as a modifier for the effect of smoking on cIMT, and other novel variants modify smoking’s impact on carotid plaque burden, illustrating complex gene-environment interactions.[10]Long non-coding RNAs also function as regulatory elements in cardiovascular disorders.[20]
Extracellular Matrix Remodeling and Tissue Integrity
Section titled “Extracellular Matrix Remodeling and Tissue Integrity”The integrity and remodeling of the extracellular matrix (ECM) are fundamental to the pathophysiology of carotid atherosclerosis.[6] Connective tissue remodeling, involving components like collagen IV (COL4A1/COL4A2) and peptidyl lysine oxidases (LOXL1, LOXL4), is crucial for organizing collagen fibrils within the arterial wall.[6] Other essential ECM components include fibrillin-1 (FBN1), which is associated with connective tissue disorders, and fibronectin-1 (FN1).[6] Enzymes that maintain or degrade the ECM also play a significant role. Metalloproteinases such as ADAMTS9 and MMP24 are involved in ECM maintenance and remodeling.[6] ADAMTS9, for example, cleaves proteoglycans like versican (VCAN), a key structural component of the ECM, and has been implicated in antiangiogenic activity and interactions with smoking in coronary artery calcification.[1]Disruptions in these homeostatic processes, including vascular calcification which can be suppressed by inhibitors like dorsomorphin homologue 1, contribute to arterial wall stiffening and disease progression.[21]
Lipid Metabolism and Cellular Homeostasis
Section titled “Lipid Metabolism and Cellular Homeostasis”Carotid atherosclerosis involves complex metabolic pathways, particularly concerning lipid handling and cellular energy balance.[22] Genes related to lipid pathways, such as _LDLR_, are strongly associated with carotid plaque and coronary heart disease, highlighting the critical role of cholesterol regulation in disease development.[13]Genome-wide association studies indicate that genes influencing carotid plaque burden are enriched in terms related to lipoprotein metabolism and cholesterol efflux, underscoring the importance of lipid transport mechanisms in preventing plaque accumulation.[13] _ABC_(ATP-binding cassette) transport proteins are crucial for mediating lipid efflux, and their function is a key area of investigation in cardiovascular disease, influencing the cellular balance of lipids within the arterial wall.[23]
Inflammation and Immune Cell Activation
Section titled “Inflammation and Immune Cell Activation”Atherosclerosis is fundamentally an inflammatory disease, characterized by the activation and accumulation of immune cells within the arterial wall.[24] Circulating and intraplaque neutrophils contribute to this inflammatory milieu by producing pro-inflammatory cytokines like _IL-8_, vascular endothelial growth factor (_VEGF_), and elastase, which perpetuate vascular damage and remodeling.[18]The cytokine_IL5_ has been implicated in carotid plaque burden, particularly in men, suggesting a sex-specific role in the inflammatory response that drives plaque progression.[15] Furthermore, the gene _TBC1D8_, involved in cellular metabolism and inflammation processes, shows differential expression in macrophages from atherosclerotic plaques, with its regulation tied to the inflammatory status of patients and influenced by factors like _TNF_.[25]
Vascular Remodeling and Extracellular Matrix Dynamics
Section titled “Vascular Remodeling and Extracellular Matrix Dynamics”The structural integrity and remodeling of the arterial wall are critical in carotid atherosclerosis, with genes associated with carotid plaque often enriched in terms related to fibroblast activity and connective tissue remodeling.[13] Key extracellular matrix (ECM) components, including collagen IV (_COL4A1_/_COL4A2_), fibrillin-1 (_FBN1_), and fibronectin-1 (_FN1_), as well as enzymes like peptidyl lysine oxidases (_LOXL1_ and _LOXL4_), are involved in organizing collagen fibrils and maintaining ECM structure.[6] Metalloproteinases such as _ADAMTS9_ and _MMP24_ also play roles in ECM maintenance and remodeling, with _ADAMTS9_ known for cleaving the proteoglycan versican (_VCAN_) and exhibiting antiangiogenic activity.[6]
Intracellular Signaling and Transcriptional Control
Section titled “Intracellular Signaling and Transcriptional Control”Intracellular signaling cascades are central to the cellular responses underlying carotid atherosclerosis, involving receptor activation and downstream transcription factor regulation. The_BMP2-Smad1/5/8_ signaling pathway is implicated in vascular calcification, a process that can be modulated by external factors like conditioned medium from mesenchymal stem cells.[26] Genetic variants in _BMPR1B_, a bone morphogenetic protein receptor, are predictive for carotid intima-media thickness, indicating its regulatory role in arterial wall health.[19] A _cAMP_-dependent pathway, involving _PRKAR2B_, a regulatory subunit of cAMP-dependent protein kinase, plays a part in adenosine-induced apoptosis of arterial smooth muscle cells, influencing cell fate within the vessel wall.[13] Furthermore, the _Myc/Max/Mad_ network of transcription factors, including _c-Myc_ oncoprotein, regulates cell cycle events and gene expression, with _Mad1_ recruiting _RBP2_ for transcriptional repression of genes like _telomerase reverse transcriptase_.[27]
Genetic Susceptibility and Environmental Interactions
Section titled “Genetic Susceptibility and Environmental Interactions”Carotid atherosclerosis development is significantly influenced by the interplay between genetic predispositions and environmental factors, leading to pathway dysregulation and compensatory mechanisms. Genome-wide association studies have identified various genetic loci linked to carotid intima-media thickness (cIMT) and carotid plaque, often involving genes related to cellular signaling, lipid metabolism, and blood pressure homeostasis.[22] Specific gene-environment interactions, such as those involving _TBC1D8_ and _RCBTB1_ with smoking, modify the risk for cIMT and plaque burden, highlighting how external stressors can alter gene expression and cellular processes.[25] Genetic variants in genes like _LEKR1_ and _GALNT10_also modulate sex-specific differences in cIMT, indicating complex regulatory mechanisms that contribute to disease heterogeneity.[17] The _KIAA1462_gene, involved in endothelial cell-cell junctions and pathological angiogenesis, demonstrates shared genetic effects with carotid and coronary atherosclerosis, suggesting common underlying mechanisms across vascular beds.[13]
Diagnostic and Prognostic Utility
Section titled “Diagnostic and Prognostic Utility”Carotid atherosclerosis, characterized by arterial wall thickening and plaque development, has a long preclinical phase that can span decades before the symptomatic presentation of major cardiovascular events like myocardial infarction and ischemic stroke.[6]Early detection of atherosclerotic plaque formation is crucial for identifying individuals at high risk of these severe outcomes, which are leading causes of mortality and disability.[6]Noninvasive imaging techniques, particularly ultrasound measurement of carotid artery intima-media thickness (cIMT) and carotid plaque presence, serve as widely accepted indices of subclinical atherosclerosis severity.[8]Increased cIMT and the presence of carotid plaque have been consistently associated with a higher risk of future cardiovascular events, including coronary heart disease (CHD) and stroke.[4]While cIMT reflects general carotid artery wall thickening from various etiologies like hypertension, carotid plaque is a more specific indicator of discrete atherosclerosis.[4]Several studies suggest that carotid plaque is a stronger predictor of future cardiovascular disease risk than common cIMT, particularly for CHD outcomes.[4]These imaging markers thus offer significant prognostic value for predicting disease progression and long-term cardiovascular implications.[4]
Risk Stratification and Treatment Guidance
Section titled “Risk Stratification and Treatment Guidance”The identification of subclinical carotid atherosclerosis through methods like B-mode ultrasound allows for effective risk stratification, pinpointing individuals who would benefit most from preventive strategies.[2]Genetic predisposition plays a significant role in atherosclerosis risk, with numerous genetic loci identified for carotid plaque and cIMT.[4] Genome-wide association studies (GWAS) have revealed susceptibility loci for cIMT and carotid plaque, providing insights into the genetic architecture underlying these traits.[4]Integrating traditional clinical risk factors—such as age, sex, BMI, smoking status, hypertension, and type 2 diabetes—with imaging-defined measures of carotid atherosclerosis enables personalized medicine approaches.[9]This comprehensive risk assessment can guide treatment selection and monitoring strategies, including lifestyle modifications, pharmacotherapy (e.g., statins), or more intensive interventions for high-risk individuals.[2] The use of standardized carotid ultrasound protocols, including automated computerized edge tracking software, enhances the precision and reliability of these measurements for clinical decision-making.[3]
Comorbidities and Genetic Associations
Section titled “Comorbidities and Genetic Associations”Carotid atherosclerosis frequently coexists with and is genetically correlated with other major cardiovascular conditions. There is a strong genetic correlation between carotid plaque and cIMT with coronary heart disease (CHD) and ischemic stroke.[1]For instance, both coronary artery disease (CAD) and carotid plaques share genetic risk loci, such as the 9p21 locus.[2]Pathway analyses indicate that cIMT loci are enriched in lipoprotein-related terms and cholesterol efflux, while carotid plaque genes are associated with fibroblast terms, suggesting distinct yet overlapping pathophysiological mechanisms.[1]Subclinical atherosclerosis, as detected by carotid ultrasound, is also relevant in the context of specific comorbidities, such as type 2 diabetes and rheumatoid arthritis, where it can be a more sensitive indicator of cardiovascular risk than other measures like coronary artery calcification scores.[28] Genetic studies have further identified candidate genes like ADAMTS9, LOXL4, CCDC71L, PRKAR2B, and KIAA1462that show shared genetic influences between cIMT or carotid plaque and CHD/stroke outcomes, highlighting overlapping phenotypes and providing etiological insights into disease mechanisms.[1]
Frequently Asked Questions About Carotid Atherosclerosis
Section titled “Frequently Asked Questions About Carotid Atherosclerosis”These questions address the most important and specific aspects of carotid atherosclerosis based on current genetic research.
1. My dad had a stroke; will I get carotid plaque too?
Section titled “1. My dad had a stroke; will I get carotid plaque too?”Yes, your family history significantly increases your risk. Genetic predisposition plays a strong role in carotid atherosclerosis, with studies estimating carotid plaque prevalence is about 50% heritable. This means if close relatives like your dad had severe outcomes like a stroke due to plaque, you have a higher genetic likelihood of developing it yourself.
2. Can my healthy lifestyle overcome “bad genes” for artery plaque?
Section titled “2. Can my healthy lifestyle overcome “bad genes” for artery plaque?”A healthy lifestyle can definitely help, but genetics are a significant factor. While genetic predisposition is strong, with heritability of carotid plaque area estimated around 69%, lifestyle factors are also relevant. By focusing on healthy habits, you can mitigate some of your genetic risk, but it might not completely eliminate it.
3. Why do some friends get clogged arteries but others avoid it?
Section titled “3. Why do some friends get clogged arteries but others avoid it?”A large part of that difference can be explained by genetics. There’s a strong genetic predisposition to atherosclerosis, with many genetic variants linked to how plaque forms and progresses. These variations influence things like lipid metabolism and blood pressure regulation, making some individuals naturally more susceptible to plaque buildup than others, even with similar lifestyles.
4. Can I have this plaque problem for a long time without knowing it?
Section titled “4. Can I have this plaque problem for a long time without knowing it?”Yes, you absolutely can. Carotid atherosclerosis often has a long preclinical phase, meaning plaque can accumulate and thicken artery walls for many years without causing any noticeable symptoms. This is why non-invasive methods like ultrasound are vital for early detection, even before you feel unwell.
5. Are women’s artery problems more linked to their genes than men’s?
Section titled “5. Are women’s artery problems more linked to their genes than men’s?”Yes, research suggests there are sex-specific genetic influences on atherosclerosis. Genetic factors might have a stronger impact on plaque development in women, while non-genetic factors like BMI could be more relevant in men. Specific genes, likeABCC1 and FPR1, have even been associated with carotid plaque in women.
6. I’m not overweight; can I still have hidden carotid plaque?
Section titled “6. I’m not overweight; can I still have hidden carotid plaque?”Yes, absolutely. While being overweight can be a risk factor, especially for men, carotid atherosclerosis can develop regardless of your weight. Genetic predisposition plays a significant role in plaque formation by influencing factors like lipid metabolism and cellular signaling, so you can still be at risk even if you maintain a healthy weight.
7. Is a genetic test useful to know my personal artery risk?
Section titled “7. Is a genetic test useful to know my personal artery risk?”Yes, genetic testing could be useful in understanding your personal risk. Genome-wide association studies have identified many genetic locations associated with both carotid artery wall thickness and plaque. Knowing your specific genetic variants could help assess your individual risk for developing carotid atherosclerosis and related cardiovascular events, allowing for earlier preventative strategies.
8. My sibling has high blood pressure, but I don’t. Am I still at risk?
Section titled “8. My sibling has high blood pressure, but I don’t. Am I still at risk?”Yes, you could still be at risk for carotid plaque. While high blood pressure is a significant factor, genetic predisposition to atherosclerosis is strong and can manifest differently, even among siblings. Shared genetic risk factors for conditions like high blood pressure and plaque are common, meaning your sibling’s condition might signal a family genetic susceptibility that could affect you in other ways.
9. Does my family’s ethnic background change my artery plaque chances?
Section titled “9. Does my family’s ethnic background change my artery plaque chances?”Yes, it can. Many large-scale genetic studies on carotid atherosclerosis have primarily focused on populations of European ancestry. This means findings might not fully apply to other ethnic groups, and there could be ancestry-specific genetic variants or different effect sizes influencing your risk based on your family’s background.
10. Is finding plaque in my neck arteries worse than just thick walls?
Section titled “10. Is finding plaque in my neck arteries worse than just thick walls?”Yes, in terms of predicting future health problems, finding actual plaque is generally considered more serious. While both thick artery walls (cIMT) and plaque indicate atherosclerosis, studies show that carotid plaque measures are more strongly reflective of future clinical events like heart attack and stroke compared to cIMT alone.
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
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[3] Dong C et al. “Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: a genome-wide interaction study.” Atherosclerosis.
[4] Bis JC 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.
[5] 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, vol. 8, no. Suppl 1, 2007, p. S4.
[6] Wai Yeung, M et al. “Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals.” Arterioscler Thromb Vasc Biol, vol. 42, no. 4, 2022, pp. 484-97. PMID: 34852643.
[7] Palmer MR et al. “Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.” Genet Epidemiol.
[8] Gummesson, A et al. “A genome-wide association study of imaging-defined atherosclerosis.”Nat Commun, vol. 15, no. 1, 2024, p. 2489. PMID: 40164586.
[9] Lu, Y et al. “Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes.”Circ Genom Precis Med, vol. 14, no. 4, 2021, p. e003260. PMID: 34241534.
[10] Della-Morte D et al. “Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics.” J Neurol Sci.
[11] Boua, P. R., et al. “Genetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans.”Nat Commun, vol. 13, 2022, p. 949.
[12] Della-Morte, D et al. “Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics.” J Neurol Sci, vol. 344, no. 1-2, 2014, pp. 27–31. PMID: 24954085.
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[17] Dong, C et al. “Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: a genome-wide interaction study.” Atherosclerosis, vol. 240, no. 1, 2015, pp. 110-18. PMID: 25898001.
[18] Marino F et al. “Production of IL-8, VEGF and Elastase by Circulating and Intraplaque Neutrophils in Patients with Carotid Atherosclerosis.”PLoS.
[19] Wu Y-J et al. “Common Genetic Variants on Bone Morphogenetic Protein Receptor Type IB (BMPR1B) Gene Are Predictive for Carotid Intima-Media Thickness.”Circ J.
[20] Xiong Y et al. “Beyond the silence: a comprehensive exploration of long non-coding RNAs as genetic whispers and their essential regulatory functions in cardiovascular disorders.”Curr. Probl. Car-diol.
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[23] Schumacher T, Benndorf RA. “ABC Transport Proteins in Cardiovascular Disease-A Brief Summary.”
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[28] 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, vol. 70, no. 1, 2018, pp. 58-66. PMID: 30251476.