Coronary Atherosclerosis

Coronary atherosclerosis is a chronic, progressive inflammatory disease characterized by the buildup of plaque within the arteries that supply blood to the heart. This process, which can develop insidiously over decades, is the primary underlying cause of coronary heart disease (CHD), also known as coronary artery disease^[1]. CHD represents a complex and heterogeneous group of cardiovascular diseases and is a leading cause of death and morbidity in industrialized nations ^[2].

Biologically, coronary atherosclerosis involves the accumulation of lipids, inflammatory cells, and fibrous tissue within the arterial walls, forming atherosclerotic plaques^[3]. These plaques can harden and narrow the arteries, restricting blood flow, or they can rupture, leading to the formation of blood clots that can block the artery entirely. Research has identified genomic regions associated with common carotid intima-media thickness (cIMT) and carotid plaque, mapping to genes related to cellular signaling, lipid metabolism, and blood pressure homeostasis. Coronary artery calcification (CAC) is a key marker of atherosclerotic plaque burden and its quantification can significantly improve the prediction of future CHD events ^[4]. Genetic factors play a substantial role, with strong heritability for CAC accounting for a significant portion of observed genetic variance.

Clinically, the progression of coronary atherosclerosis often remains asymptomatic until it reaches an advanced stage, leading to severe cardiovascular events such as myocardial infarction (heart attack) and other forms of CHD. Early detection through methods like computed tomography (CT) to measure CAC is crucial for assessing disease extent and risk. While numerous genetic factors influencing CHD have been identified through genome-wide association studies (GWAS), their full application in clinical practice for diagnosis, prognosis, and treatment is still evolving.

The social importance of coronary atherosclerosis is profound, as CHD remains a major public health challenge globally. It imposes a significant burden on healthcare systems and leads to substantial mortality and morbidity, affecting quality of life for millions. Understanding the genetic and environmental factors that contribute to coronary atherosclerosis is vital for developing effective prevention strategies, improving early diagnosis, and advancing personalized treatment approaches to mitigate its widespread impact.

Limitations

Understanding the genetic and environmental factors contributing to coronary atherosclerosis is subject to several methodological and interpretative challenges that limit the scope and generalizability of current research findings.

Study Design and Statistical Power Limitations

Many studies on coronary atherosclerosis, particularly those employing cross-sectional designs, are susceptible to inherent biases such as survival bias.^[5]This means that individuals who have survived long enough to be included in a study might not fully represent the broader population affected by the condition, potentially skewing observed associations and limiting the generalizability of findings to the entire disease spectrum. Furthermore, even large genome-wide association studies often face statistical limitations, particularly in their power to detect genetic variants with small effect sizes.^[6]This can lead to an underestimation of the genetic contribution to coronary atherosclerosis, as subtle but potentially important associations may be missed, thereby hindering a complete understanding of the disease’s genetic architecture.

Population Structure and Interpretation Challenges

The influence of population structure on genetic studies of coronary atherosclerosis represents a significant limitation when interpreting findings across diverse groups. While strategies involving admixed populations can increase sample sizes, associations identified in genomic regions exhibiting geographical differentiation require careful consideration.^[7]Such findings must be interpreted with caution, as they may reflect population-specific genetic backgrounds or stratification rather than direct causal links to the disease, potentially complicating the identification of universally applicable risk factors and mechanisms. This necessitates careful validation across independent cohorts to ensure that observed associations are robust and not merely artifacts of population differences.

Variants

Genetic variations play a crucial role in an individual’s susceptibility to coronary atherosclerosis, a condition characterized by the buildup of plaque in the arteries. Numerous single nucleotide polymorphisms (SNPs) across the genome have been identified that influence various pathways contributing to this complex disease, from lipid metabolism to vascular cell function and inflammation.

Variants in genes related to lipid metabolism are fundamental drivers of atherosclerosis. For instance, theLPAgene encodes apolipoprotein(a), a key component of lipoprotein(a) [Lp(a)], a modified form of LDL cholesterol. Elevated Lp(a) levels are a strong, independent risk factor for coronary artery disease, promoting plaque formation and inflammation. Thers10455872 variant in LPAis significantly associated with higher Lp(a) levels and increased risk of coronary atherosclerosis.^[8] Similarly, the LDLR (Low-density lipoprotein receptor) gene is vital for clearing harmful LDL cholesterol from the bloodstream. Variants within the SMARCA4-LDLR locus, such as rs142130958 and rs12151108 , can influence LDLR activity or expression, leading to higher circulating LDL cholesterol levels, a primary factor in atherosclerotic plaque accumulation. ^[9]

Other variants impact vascular cell regulation and proliferation, which are critical processes in plaque development. The CDKN2B-AS1gene, a long non-coding RNA located in a major genetic hotspot for coronary artery disease (9p21), regulates the expression of neighboring genes involved in cell cycle control and cellular aging. Variants likers1537371 , rs7857345 , and rs10757279 are strongly associated with increased CAD risk, likely by affecting the proliferation and senescence of vascular smooth muscle cells and endothelial cells. ^[9] Likewise, the PHACTR1 gene, which regulates the actin cytoskeleton and influences endothelial cell function and vascular tone, contains the rs9349379 variant, a known risk factor for coronary atherosclerosis. This variant may impact the integrity and function of blood vessel walls and contribute to arterial inflammation.^[9]

Several genetic loci influence the structural integrity and cellular phenotype of blood vessels. CELSR2 (Cadherin EGF LAG Seven-pass G-type Receptor 2) is involved in cell adhesion and is located in a region linked to lipid levels and CAD. Variants such as rs12740374 and rs7528419 are associated with altered LDL cholesterol levels and increased risk of coronary atherosclerosis, suggesting a role in hepatic lipid metabolism or vascular cell interactions.^[9] The COL4A2 gene provides instructions for making a component of type IV collagen, a crucial structural protein in the basement membranes of blood vessels. The rs9515203 variant can affect the integrity and remodeling of the extracellular matrix within arterial walls, potentially influencing plaque stability and the vessel’s response to injury. ^[9] Furthermore, the TCF21 gene, which encodes a transcription factor essential for coronary artery development and smooth muscle cell differentiation, and its regulatory long non-coding RNA TARID, are implicated in atherosclerosis. Thers12190287 variant in this region is linked to coronary atherosclerosis by potentially disrupting the normal function and phenotype of smooth muscle cells, promoting their shift to a pro-atherogenic state, and impairing vascular repair.

Finally, variants in genes involved in broader cellular processes also contribute to atherosclerosis risk. Thers28451064 variant spans a complex locus including MRPS6, involved in mitochondrial protein synthesis, LINC00310 (a long non-coding RNA), and KCNE2, a regulatory subunit of potassium channels important for heart rhythm and vascular function. This association suggests an interplay between mitochondrial health, ion channel activity, and cellular signaling in cardiovascular health. ^[9] The AIDA gene (Apoptosis Inducing Factor Mitochondrion Associated 1), with its rs12138316 variant, plays a role in programmed cell death and mitochondrial function, influencing the survival and turnover of cells within the arterial wall. Additionally, the rs11556924 variant in the ZC3HC1 and UBE2H-DTregion is linked to coronary atherosclerosis.ZC3HC1 is a ubiquitin ligase involved in immune responses and inflammatory pathways, suggesting that this variant impacts the delicate balance of inflammation and cellular signaling crucial for arterial health.

Key Variants

RS ID	Gene	Related Traits
rs10455872	LPA	myocardial infarction lipoprotein-associated phospholipase A(2) measurement response to statin lipoprotein A measurement parental longevity
rs1537371 rs7857345 rs10757279	CDKN2B-AS1	asthma, cardiovascular disease asthma, endometriosis angina pectoris HMG CoA reductase inhibitor use measurement coronary artery disease
rs9349379	PHACTR1	coronary artery disease migraine without aura, susceptibility to, 4 migraine disorder myocardial infarction pulse pressure measurement
rs12740374 rs7528419	CELSR2	low density lipoprotein cholesterol measurement lipoprotein-associated phospholipase A(2) measurement coronary artery disease body height total cholesterol measurement
rs9515203	COL4A2	coronary artery disease carotid artery thickness age at diagnosis, coronary atherosclerosis measurement angina pectoris myocardial infarction
rs28451064	MRPS6, LINC00310, KCNE2	myocardial infarction coronary artery disease BMI-adjusted waist-hip ratio waist-hip ratio pulse pressure measurement
rs142130958 rs12151108	SMARCA4 - LDLR	anxiety measurement, low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement total cholesterol measurement esterified cholesterol measurement, high density lipoprotein cholesterol measurement free cholesterol measurement, low density lipoprotein cholesterol measurement
rs12138316	AIDA	FEV/FVC ratio heart rate coronary atherosclerosis
rs11556924	ZC3HC1, UBE2H-DT	coronary artery disease myocardial infarction diastolic blood pressure platelet count platelet crit
rs12190287	TARID, TCF21	coronary artery disease stroke, coronary artery disease large artery stroke, coronary artery disease serum creatinine amount glomerular filtration rate

Classification, Definition, and Terminology

Coronary atherosclerosis is a progressive condition characterized by the accumulation of fatty plaques, cholesterol, and other substances within the inner lining of the coronary arteries. This process results in the hardening and narrowing of these arteries, which supply blood to the heart muscle, and can ultimately lead to various clinical manifestations.

• Coronary Artery Disease (CAD)Coronary artery disease is a broad term encompassing conditions that result from coronary atherosclerosis. It is a significant public health concern, identified as a leading cause of illness, disability, and mortality, particularly among older individuals^[10]; ^[11]. The development of CAD typically follows a series of pathological changes in the coronary arteries. In some research contexts, CAD can be categorized based on the degree of coronary artery stenosis. For example, patients with no visible lesions in any of the four coronary arteries may be classified as a control group (e.g., CAD category 1), while those exhibiting coronary artery stenosis can be grouped into categories such as CAD category 2, which may include individuals with up to 50% stenosis, considered moderate.

• Coronary Heart Disease (CHD)Coronary heart disease is a term often used interchangeably with or as a consequence of coronary artery disease, representing the clinical events and symptoms that arise due to the atherosclerotic process affecting the heart’s blood supply. Understanding the mechanisms of atherosclerosis is vital for developing effective strategies for the prediction, prevention, and treatment of CHD.

• Coronary Artery Stenosis Coronary artery stenosis specifically refers to the narrowing or constriction of the coronary arteries. This narrowing is typically caused by the buildup of atherosclerotic plaques, which can reduce blood flow to the myocardium (heart muscle). The degree of stenosis is a critical factor in classifying the severity of CAD.

• Coronary Artery Calcification (CAC)Coronary artery calcification involves the deposition of calcium within the walls of the coronary arteries. CAC is a measurable indicator of the presence and extent of atherosclerosis. The quantity of CAC can be assessed using specific methods, such as the Agatston method. Prior studies have demonstrated a highly significant association between CAC and overall cardiovascular risk^[11].

• Myocardial Infarction (MI) Myocardial infarction, commonly known as a heart attack, is a serious clinical event that occurs when blood flow to a part of the heart muscle is severely reduced or blocked, often due to a ruptured atherosclerotic plaque and subsequent clot formation in a coronary artery. This blockage can lead to the death of heart muscle tissue.

Coronary atherosclerosis, a condition where plaque builds up in the arteries supplying the heart, can manifest in various ways, ranging from no apparent symptoms to life-threatening events.

Typical Presentations

The accumulation of plaque can lead to narrowing of the coronary arteries. A common and severe presentation is a ^[12], often referred to as a heart attack.

Measurement Approaches

The presence and severity of coronary atherosclerosis can be assessed through several methods:

• Coronary Artery Calcification (CAC): ^[12]is a measure of subclinical atherosclerosis. It can be quantified using^[13]. This method allows for the identification of the condition even in ^[13].
• Cardiovascular Risk Factors: Various factors are associated with coronary atherosclerosis and can be measured as indicators, including^[12]. Other measurable traits include ^[12]. Smoking status is also a significant risk factor can influence the characteristics of the condition.
• Risk Factor Prevalence: The prevalence of cardiovascular risk factors like ^[12] can differ among patient groups. For instance, ^[12]. Smoking habits also vary among affected individuals , highlighting that the absence of symptoms does not rule out the disease.

Causes of Coronary Atherosclerosis

Coronary atherosclerosis is a multifaceted condition influenced by both genetic predispositions and various environmental factors.

Genetic Factors

Genetic factors contribute to the risk of developing coronary atherosclerosis. A strong family history of premature cardiovascular disease indicates a genetic component^[14]. Specific genetic associations identified include:

• Single nucleotide polymorphisms (SNPs) found within the lipoprotein lipase gene ^[14].
• Genomic regions containing SNPs that are involved in cellular signaling, lipid metabolism, and blood pressure regulation. These regions have been linked to coronary artery disease^[14].

Environmental Factors

Environmental and lifestyle elements also play a role in the development of coronary atherosclerosis. These factors include:

• Acculturation ^[4].
• Socioeconomic position ^[4].

Biological Background

Coronary artery disease (CAD), also known as coronary heart disease (CHD), is a complex and diverse cardiovascular disease. It is a chronic condition that develops gradually throughout life, often progressing to an advanced stage before symptoms become apparent^[2]. The critical underlying process in its development is atherosclerosis, a multifactorial condition^[15]. Atherosclerosis is recognized as an inflammatory disease^[3].

The formation and progression of atherosclerotic plaque, along with its stability, involve several fundamental biological processes ^[16]. Genetic regulation of these processes plays a significant role in the development of CAD and myocardial infarction ^[16].

Key cellular and molecular pathways involved in atherosclerosis include:

• Initiation: The retention of lipoproteins in the subendothelial space is considered an initiating process ^[17].
• Plaque Development: The pathology involves the development of plaques and their responses to medical treatments ^[1].
• Inflammation and Immunity:
  • Atherosclerosis involves the immune system^[18].
  • Adaptive immunity also plays a role in its mechanisms ^[19].
  • NLRP3 inflammasomes are necessary for atherogenesis and are activated by cholesterol crystals ^[20].
• Metabolism and Signaling:Genes related to cellular signaling, lipid metabolism, and blood pressure regulation are associated with atherosclerosis^[15]. For instance, genetic variants (SNPs) in the lipoprotein lipase gene have shown an association ^[16].

Pathways and Mechanisms

Coronary atherosclerosis is a complex disease process that contributes significantly to heart disease, a leading cause of illness, disability, and death^[21]. The manifestation of coronary artery disease follows a series of physiological events^[21]. Research into the mechanisms of coronary atherosclerosis involves identifying genetic variants that influence metabolism and characterizing their effects on nearby genes^[21]. This approach utilizes the study of metabolic networks to uncover the underlying physiological pathways involved ^[21].

Several distinct metabolic networks have been identified, each representing various metabolic pathways that may play a role in atherosclerosis:

• Cholesterol and Lipoprotein Metabolism: One network is closely associated with cholesterol metabolism and the activity of apoB-containing lipoproteins ^[21].
• Amino Acid and Triglyceride Metabolism:Another network encompasses branched-chain and aromatic amino acids, alongside large triglyceride (TG)-rich VLDL particles and serum triglycerides^[21].
• HDL Metabolism: Two distinct networks capture the dynamics of HDL-metabolism, specifically differentiating between larger and smaller HDL particles ^[21].
• Lipid Poly-unsaturation, Ketone Bodies, and Glucose-Alanine Cycle:Other networks are related to lipid poly-unsaturation, the production of ketone bodies, and the glucose-alanine cycle, indicating their potential involvement in metabolic regulation relevant to the disease^[21].
• Renal Function:A specific network has been linked to renal function, suggesting a connection between kidney health and atherosclerosis pathways^[21].
• Fatty Acid Composition and LDL Diameter: Additional networks represent measures of fatty acid chain length and composition, the mean diameter of LDL particles, and the double-bonding of fatty acid chains ^[21].
• Urea and Acetate: Simple networks involving urea and acetate also contribute to the metabolic profile ^[21].

These metabolic networks, identified through comprehensive metabolomic profiling, provide insights into the molecular and physiological mechanisms that contribute to the development and progression of coronary atherosclerosis^[21]. The pathophysiology of coronary artery disease itself is a well-established field of study^[22].

Population Studies

Coronary atherosclerosis is a significant public health concern, with numerous epidemiological and cohort studies providing insight into its prevalence and risk factors across different populations. Heart disease statistics from the American Heart Association offer updates on its impact^[23]; ^[10]. Globally, coronary atherosclerosis contributes to the overall burden of disease^[24].

Early evidence of coronary artery disease has been observed in young populations. Studies on American soldiers killed in Korea and Vietnam revealed the presence of coronary disease, even in young combat casualties^[25]; ^[26]. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study further detailed the natural history of aortic and coronary atherosclerotic lesions in youth^[27].

Longitudinal cohort studies have been instrumental in understanding the development and progression of coronary atherosclerosis. The Framingham Study, initiated as an approach to longitudinal studies in a community, has followed multiple generations, including the Framingham Offspring Study and the Third Generation Cohort, to investigate coronary heart disease in families and track cardiovascular risk factors^[28]; ^[29]; ^[30]. Similarly, the Reykjavik Study, an age, gene/environment susceptibility study, has contributed to understanding the epidemiology and characteristics of conditions like unrecognized myocardial infarction ^[31]; ^[32]. The Rotterdam Study is another large population-based cohort study designed to investigate chronic diseases in the elderly, including cardiovascular diseases ^[33].

Population-based studies have characterized typical demographics and risk factor prevalence for individuals with coronary artery disease. For instance, one population-based study reported an average age of 55.3 ± 10.8 years, with females constituting 50.5% of the participants. Common cardiovascular risk factors identified in this population included hypertension (51.0%), dyslipidemia (26.8%), diabetes mellitus (26.8%), and obesity (22.4%). Smoking habits were also noted, with 18.6% current smokers, 34.2% ex-smokers, and 47.2% who had never smoked. The average Body Mass Index (BMI) was 27.0 ± 4.7 kg/m²^[12].

Frequently Asked Questions About Coronary Atherosclerosis

These questions address the most important and specific aspects of coronary atherosclerosis based on current genetic research.

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1. My dad had a heart attack early; will I get one too?

Yes, having a close relative with early heart disease significantly increases your risk because genetic factors play a strong role in coronary atherosclerosis. Variants in genes likeLPA, which affects harmful cholesterol levels, can be passed down. While genetics predispose you, lifestyle choices can help manage this inherited risk.

2. I eat healthy and exercise; why might I still be at risk?

Even with a healthy lifestyle, your genetic makeup can still put you at risk. Strong heritability for conditions like coronary artery calcification (CAC) means some people are genetically more prone to plaque buildup, regardless of their habits. For example, specific variants can influence how your body handles lipids or inflammation, making you more susceptible.

3. Can I really prevent heart problems if they run in my family?

While you can’t change your genes, you absolutely can significantly reduce your risk. Lifestyle factors like diet and exercise interact with your genetics. Understanding your family history can prompt earlier screening, like CT scans for coronary artery calcification, allowing for early intervention and personalized prevention strategies.

4. Why did my doctor suggest a special scan for my heart?

Your doctor likely suggested it because coronary atherosclerosis often develops silently, showing no symptoms until it’s advanced. A CT scan to measure coronary artery calcification (CAC) is a key way to detect plaque buildup early, even before you feel unwell, and it greatly improves predicting future heart events. This helps assess your true disease extent and risk.

5. Does my background affect my chance of getting clogged arteries?

Yes, your ethnic or population background can influence your risk. Genetic studies have found that associations identified in one group may need careful validation in others due to differences in population structure. This means certain genetic risk factors for coronary atherosclerosis might be more prevalent or expressed differently in various ancestral groups.

6. Why don’t I feel sick if my arteries are getting blocked?

Coronary atherosclerosis is a chronic, progressive disease that often remains asymptomatic for decades. Plaque builds up gradually, and you typically won’t experience symptoms until the arteries are significantly narrowed or a plaque ruptures, leading to a serious event like a heart attack. Early detection methods like CAC scans are crucial because of this silent progression.

7. Is a DNA test useful to know my heart risk?

Genetic tests can identify variants, like those in the LPAgene, that increase your risk for coronary atherosclerosis by affecting things like lipoprotein(a) levels. While these tests offer insights into your genetic predisposition, their full application in routine clinical practice for precise diagnosis and treatment is still developing. They can be part of a broader risk assessment.

8. Why do some people get clogged arteries but live long?

The progression and clinical impact of coronary atherosclerosis can vary greatly among individuals. While plaque buildup is a risk factor, not everyone with it will experience severe events. This variability is influenced by a complex interplay of your specific genetic profile, other lifestyle factors, and how your body manages the disease over time, sometimes without acute blockages.

9. My sibling has heart disease, but I don’t; why the difference?

Even identical twins can have different health outcomes, and for siblings, genetic inheritance isn’t always identical, plus lifestyle choices differ. While you share many genes, specific genetic variants influencing lipid metabolism or inflammation might be present in one sibling but not the other, leading to different susceptibilities to coronary atherosclerosis. Environmental factors also play a huge role.

10. Does what I eat really matter if my family has bad genes?

Absolutely, what you eat matters immensely, even with a strong family history. While genetics, like variants affecting LDLRfunction or Lp(a) levels, predispose you, your diet directly influences factors like cholesterol and inflammation. A healthy diet can help mitigate the expression of genetic risks, reducing your overall chance of developing severe coronary atherosclerosis.

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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.

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