Coronary Artery Disease

Coronary Artery Disease (CAD) is a common and complex condition characterized by the narrowing or blockage of the coronary arteries, which are vital blood vessels that supply oxygen-rich blood to the heart muscle. This condition is primarily caused by atherosclerosis, a process where fatty deposits, known as plaques, build up on the inner walls of these arteries, leading to hardening and reduced blood flow.

CAD and its primary complication, myocardial infarction (heart attack), are leading causes of death and disability worldwide. While lifestyle and environmental factors play a significant role in its development, research indicates that these diseases also cluster in families, suggesting a substantial inherited component. Genetic variation is understood to influence the risk of CAD both directly and through its effects on known risk factors such as hypertension, diabetes, and hypercholesterolemia.

From a biological perspective, the development of atherosclerosis involves intricate processes including inflammation, lipid accumulation, and cellular changes within the arterial walls. Genetic factors can modulate these pathways, affecting an individual’s susceptibility to plaque formation and progression. Genome-wide studies have identified several genetic loci that may influence susceptibility to CAD, with a notable association found on chromosome 9p21.3. These studies suggest that while the effect of individual genetic variants may be modest, their combined influence can substantially affect an individual’s risk of developing CAD.

Clinically, CAD can lead to symptoms such as angina (chest pain), shortness of breath, and fatigue. Its most severe manifestation is a myocardial infarction, which occurs when blood flow to a part of the heart muscle is completely blocked, causing heart tissue damage. The ability to identify genetic predispositions offers potential avenues for improved overall coronary risk prediction and, in the long term, better prevention and treatment strategies.

The widespread prevalence and serious health consequences of CAD underscore its significant social importance. It places a considerable burden on healthcare systems globally, impacting quality of life, productivity, and life expectancy for millions. Understanding the genetic underpinnings of CAD is crucial for developing more personalized approaches to screening, prevention, and treatment, ultimately aiming to reduce its global impact.

Limitations

Methodological and Statistical Constraints

Current research into the genetics of coronary artery disease faces several methodological and statistical challenges that influence the interpretation and completeness of findings. Genome-wide association studies (GWAS) involve a large number of statistical tests, which can make it difficult to distinguish between true genetic associations and false positives.^[1] This necessitates rigorous follow-up, such as staged designs and replication in independent samples, to increase the statistical confidence of identified associations. ^[1] Furthermore, the use of conservative statistical methods, such as the Cochran–Armitage test for trend, may lead to some genuine genetic loci being overlooked. ^[1]

Technical limitations in genotyping platforms also contribute to these constraints; for example, a substantial percentage of variants typed by arrays may not be evaluable, leaving gaps in the comprehensive assessment of genetic variation. ^[1]These unaddressed variants and the conservative analytical approaches suggest that current studies may have missed several important genetic loci influencing coronary artery disease.^[1]Consequently, despite the identification of new genetic regions, the full genetic architecture of the disease remains incompletely understood, highlighting the need for continued refinement of study designs and analytical strategies.^[1]

Generalizability and Phenotypic Scope

The generalizability of genetic findings for coronary artery disease can be limited by the characteristics of the study populations. For instance, studies that specifically recruit individuals with a strong family history of premature coronary artery disease may enhance the power to detect genetic associations, but this approach can also inflate the estimated population attributable risks compared to sporadic cases.^[1] Therefore, the applicability of these risk estimates to the broader population with typical onset or less severe family history requires careful consideration and further investigation in more diverse cohorts. ^[1]

Moreover, the current scope of genetic investigation often focuses on coronary artery disease as a primary outcome, which might not fully capture the broader spectrum of related cardiovascular conditions. Future studies are needed to explore whether identified genetic loci also associate with other forms of atherosclerotic disease or with various established cardiovascular risk factors and biomarkers.^[1]A more comprehensive phenotyping approach would help elucidate the pleiotropic effects of these genetic variants and their roles across the continuum of cardiovascular health, providing a more complete picture of their clinical relevance.^[1]

Persistent Knowledge Gaps in Genetic Architecture

Despite significant advances in identifying genetic associations, a substantial gap persists in fully understanding the molecular genetic basis of coronary artery disease and myocardial infarction. Even with evidence of complex diseases clustering in families and suggesting a strong genetic component, robust molecular evidence for many genetic associations remains to be obtained.^[1] This indicates that the identified loci represent only a part of the genetic landscape, with many other contributing genetic factors potentially yet to be discovered. ^[1]

Addressing this missing heritability and deepening mechanistic understanding requires focused follow-up research. Such efforts include fine mapping of associated genomic regions to pinpoint causal variants and thorough investigation of candidate genes within these loci to clarify their biological functions in disease pathogenesis.^[1]These ongoing investigations are crucial for translating genetic associations into a deeper comprehension of disease mechanisms and ultimately, for developing more effective prevention and treatment strategies.^[1]

Variants

Genetic variations play a crucial role in an individual’s susceptibility to complex diseases like coronary artery disease (CAD). The variants discussed here are located in genes involved in diverse biological processes, including lipid metabolism, blood coagulation, inflammation, and cell cycle regulation, all of which contribute to the development and progression of atherosclerosis and its clinical manifestations. Understanding these genetic influences provides insights into disease mechanisms and potential therapeutic targets.

Variants in the ABCG5 and ABCG8 genes, such as rs13427362 (ABCG5), rs75331444 , rs4299376 , and rs7598542 (ABCG8), are critical for sterol transport. These genes encode ATP-binding cassette (ABC) transporters that form a functional heterodimer, primarily expressed in the liver and intestine, where they regulate the efflux of cholesterol and plant sterols from the body. Specific alleles can influence the efficiency of sterol excretion, leading to altered blood lipid profiles, including levels of LDL cholesterol and plant sterols, thereby impacting the risk of developing atherosclerotic plaques. Similarly, variants in theLPA gene, including rs10455872 , rs55730499 , and rs140570886 , significantly affect the levels of lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle. High Lp(a) concentrations are a strong, independent risk factor for CAD due to its pro-atherogenic and pro-thrombotic properties, and these variants are key determinants of circulating Lp(a) concentrations.

Other genetic variations influence the coagulation cascade and inflammatory responses. The F11 gene, with variant rs4253417 , encodes coagulation Factor XI, a protein central to the intrinsic pathway of blood clotting. Alterations in Factor XI activity can modulate the risk of thrombotic events, which are a direct cause of myocardial infarction and stroke in CAD patients. Likewise, theFGB gene, represented by rs2227402 , codes for the beta chain of fibrinogen, a primary component of blood clots. Variants affecting fibrinogen levels or function can alter clot formation and stability, contributing to CAD risk. The ABO blood group system, with variants such as rs10901252 , rs687621 , and rs507666 , also plays a role, as blood types are associated with differing levels of von Willebrand factor and Factor VIII, affecting coagulation and influencing overall cardiovascular risk. Moreover, theKNG1 gene, encoding kininogen, and its regulatory long non-coding RNA HRG-AS1, with shared variant rs710446 , are involved in the kallikrein-kinin system, which influences inflammation, blood pressure, and vascular permeability, thereby indirectly affecting CAD progression.

Finally, a cluster of variants affects cellular proliferation, metabolic regulation, and general vascular health. The CDKN2B-AS1 gene, a long non-coding RNA also known as ANRIL, encompasses variants like rs2891168 , rs4977574 , and rs1333049 , notably located on chromosome 9p21.3. This region is a major genetic susceptibility locus for CAD, type 2 diabetes, and abdominal aortic aneurysm, with these variants influencing the expression of neighboring cell cycle regulatory genes (CDKN2A and CDKN2B) that control vascular smooth muscle cell proliferation and senescence, crucial processes in atherosclerosis. TheTCF7L2 gene, including variants rs35519679 , rs34872471 , and rs142827301 , is a key transcription factor in the Wnt signaling pathway, essential for glucose homeostasis and pancreatic beta-cell function. These variants are strongly linked to an increased risk of type 2 diabetes, a significant comorbidity and risk factor for CAD. TheMCF2L gene, with variant rs1046205 , encodes a guanine nucleotide exchange factor involved in activating Rho GTPases, which regulate various cellular processes including cell growth, adhesion, and migration. While its direct link to CAD is still being elucidated, these cellular functions are integral to vascular remodeling and plaque stability.

Key Variants

RS ID	Gene	Related Traits
rs10901252 rs687621 rs507666	ABO	hematocrit hemoglobin measurement von Willebrand factor quality erythrocyte volume mean corpuscular hemoglobin concentration
rs1046205	MCF2L	factor VII measurement venous thromboembolism, factor VII measurement circulating fibrinogen levels, factor VII measurement Ischemic stroke, factor VII measurement coronary artery disease
rs2891168 rs4977574 rs1333049	CDKN2B-AS1	coronary artery disease myocardial infarction asthma, cardiovascular disease Beta blocking agent use measurement Vasodilators used in cardiac diseases use measurement
rs75331444 rs4299376 rs7598542	ABCG8	serum alanine aminotransferase amount total cholesterol measurement Cholecystitis cholelithiasis coronary artery disease
rs710446	HRG-AS1, KNG1	Ischemic stroke, venous thromboembolism, stroke, Abnormal thrombosis, deep vein thrombosis, pulmonary embolism blood coagulation trait factor XI measurement ESAM/SPINT2 protein level ratio in blood AGRP/NPY protein level ratio in blood
rs35519679 rs34872471 rs142827301	TCF7L2	coronary artery disease systolic blood pressure BMI-adjusted hip circumference BMI-adjusted waist-hip ratio
rs10455872 rs55730499 rs140570886	LPA	myocardial infarction lipoprotein-associated phospholipase A(2) measurement response to statin lipoprotein A measurement parental longevity
rs4253417	F11	venous thromboembolism blood protein amount factor XI measurement pulmonary embolism factor XI measurement, circulating fibrinogen levels, tissue plasminogen activator amount, factor VII measurement
rs2227402	FGB	circulating fibrinogen levels, factor VII measurement Ischemic stroke, circulating fibrinogen levels venous thromboembolism, circulating fibrinogen levels coronary artery disease
rs13427362	ABCG5	coronary artery disease

Classification, Definition, and Terminology

Coronary artery disease (CAD), also referred to as coronary atherosclerosis, is a chronic degenerative condition characterized by the deposition of lipid and fibrous matrix within the walls of the coronary arteries, leading to the formation of atheromatous plaques Samani et al. This condition may manifest without any noticeable symptoms or present clinically as angina pectoris or an acute myocardial infarction Samani et al. The development of CAD is a complex process involving endothelial dysfunction, oxidative stress, and inflammation, all of which contribute to the progression and instability of atherosclerotic plaques Samani et al. In addition to lifestyle and environmental factors, genetic predispositions play a significant role in the etiology of CAD Samani et al.

Atheromatous Plaques: Deposits composed of lipid and fibrous matrix that form within the walls of the coronary arteries, a hallmark of CAD Samani et al.
Major CHD Events:A classification that includes recognized myocardial infarction, coronary insufficiency, and death specifically attributed to coronary heart disease (CHD) Samani et al.
Myocardial Infarction (MI): Diagnosed when at least two of three clinical criteria are met: the presence of new diagnostic Q-waves on an electrocardiogram (ECG), prolonged ischemic chest discomfort, and elevated serum biomarkers indicative of myocardial necrosis Samani et al.
CHD Death: Determined after a thorough review of available records, when the cause of death is highly probable to be CHD and no other cause can be definitively identified Samani et al.
Major Atherosclerotic CVD Events:A broader category encompassing major CHD events along with atherothrombotic stroke Samani et al.
Atherothrombotic Brain Infarction (Stroke): Defined as an acute-onset focal neurological deficit of vascular etiology that is non-embolic and persists for more than 24 hours, or an ischemic infarct confirmed by autopsy Samani et al.
Heart Failure (HF):Diagnosed upon the presence of at least two major criteria, or one major and two minor criteria. Major criteria include paroxysmal nocturnal dyspnea, pulmonary rales, distended jugular veins, and an enlarging heart size Samani et al.
Cardiovascular Risk Factors:Conditions or habits identified as increasing the likelihood of developing CAD, such as diabetes mellitus, hypertension, hyperlipidemia, former or current smoking, and obesity (defined by a body-mass index greater than 30) Samani et al.

Classification

For research and clinical analysis, events associated with coronary artery disease are categorized into distinct groups:

Major CHD Events:This group covers recognized myocardial infarction, coronary insufficiency, and mortality resulting from CHD Samani et al.
Major Atherosclerotic CVD Events:A comprehensive classification that includes all major CHD events as well as atherothrombotic stroke Samani et al.

Coronary Artery Disease: Signs and Symptoms

Coronary artery disease (CAD), also known as coronary atherosclerosis, is a chronic degenerative condition where lipid and fibrous matrix accumulate in the walls of the coronary arteries, forming atheromatous plaques.

Typical Presentations

CAD can present in various ways, from being clinically silent (without noticeable symptoms) to manifesting with severe cardiac events. Common presentations include:

Angina Pectoris:Chest pain or discomfort resulting from reduced blood flow to the heart.
Acute Myocardial Infarction:A heart attack, which is a sudden blockage of blood flow to the heart, causing damage to the heart muscle.
Coronary Insufficiency: A condition where the coronary arteries cannot supply enough oxygenated blood to meet the heart’s needs.
Death due to Coronary Heart Disease (CHD): In severe cases, CAD can be fatal.

Measurement Approaches

The diagnosis and assessment of CAD involve several clinical and subclinical approaches:

Myocardial Infarction Diagnosis: A myocardial infarction is typically diagnosed when at least two out of three clinical criteria are met: the presence of new diagnostic Q-waves on an electrocardiogram (ECG), prolonged ischemic chest discomfort, and elevated serum biomarkers indicating myocardial necrosis.
Validated History: CAD can be confirmed through a validated history of myocardial infarction or coronary revascularization procedures, such as coronary artery bypass surgery or percutaneous coronary angioplasty. Verification of this history often requires reviewing hospital records or documentation from the primary care physician.
Adjudication of Events:Suspected cardiovascular disease (CVD) events are reviewed and adjudicated by physician investigators, often using established criteria based on examination records, hospitalization records, and physician notes.
Subclinical Atherosclerosis Measures:Before the onset of overt symptoms, subclinical atherosclerosis can be assessed using various measures, including:
- Ankle-brachial index (ABI)
- Common carotid artery intimal medial thickness (IMT)
- Internal carotid artery IMT
- Coronary artery calcification (CAC)
- Abdominal aortic calcification

Variability

The presentation of CAD is highly variable. Individuals may experience the condition without any noticeable symptoms for extended periods (clinically silent CAD) or develop severe symptoms like angina pectoris or an acute myocardial infarction.

Causes of Coronary Artery Disease

Coronary artery disease (CAD), along with its main complication myocardial infarction, is influenced by a combination of genetic and environmental factors. Studies indicate that these complex diseases tend to run in families, suggesting a significant genetic component^[2].

Environmental Factors

Lifestyle and environmental factors play an important role in the development of CAD^[2]. Specific environmental factors are not detailed in the provided research, but epidemiological approaches have been crucial in understanding heart disease^[3].

Genetic Factors

Genetic variation is believed to influence the risk of CAD both directly and indirectly through its effects on known risk factors such as hypertension, diabetes, and hypercholesterolemia^[2]. The genetic regulation of processes fundamental to the formation, progression, and instability of atherosclerotic plaque is thought to play an important role in the development of CAD and myocardial infarction ^[2].

Several genetic loci and variants have been identified that affect susceptibility to CAD:

Chromosome 9p21.3: A powerful association with CAD has been found on chromosome 9p21.3. The strongest signal in this region is at rs1333049 , but associations are observed for single nucleotide polymorphisms (SNPs) across more than 100 kilobases^[2].
Replicated Loci: Two other loci, chromosome 6q25.1 (rs6922269 ) and chromosome 2q36.3 (rs2943634 ), were successfully replicated in studies ^[2].
Additional Loci: Further studies identified additional loci significantly associated with CAD, including chromosomes 1p13.3 (rs599839 ), 1q41 (rs17465637 ), 10q11.21 (rs501120 ), and 15q22.33 (rs17228212 ) ^[2].
Lipoprotein Lipase Gene:SNPs in the lipoprotein lipase gene have shown evidence of association with CAD in multiple studies^[2].
MEF2A:A mutation in the MEF2A gene has been linked to an inherited disorder with features of coronary artery disease^[4].
Other Variants: Other gene variants associated with myocardial infarction have been identified ^[5].

While the odds ratios for each individual genetic locus are modest, as expected for a polygenic disorder, the estimates of population attributable fractions for validated loci are substantial, both individually and in aggregate. This offers potential for improved overall coronary risk prediction ^[2].

Biological Background

Coronary artery disease (CAD) is primarily characterized by the formation and progression of atherosclerotic plaque, a process that can lead to plaque instability^[6]. Genetic factors are understood to play a significant role in regulating these biological processes and influencing the overall development of CAD and myocardial infarction ^[1].

Several molecular and cellular pathways are implicated in the underlying biology of CAD:

Atherosclerosis and Plaque Dynamics The formation, progression, and instability of atherosclerotic plaques are central to the pathology of CAD ^[6]. Specific cellular and molecular processes that are fundamental to these plaque dynamics involve genes such as DDA3, MIA (melanoma inhibitory activity), and the TGF-beta signaling pathway, particularly through Smad proteins ^[7].
InflammationInflammation is a key component in the development and progression of CAD. The interleukin-18 (IL-18) system, including the interleukin-18 gene, has been highlighted for its role in cardiovascular disease^[8]. Genetic variants influencing inflammatory pathways are also considered important contributors to CAD risk ^[1]. Genes such as ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase), which are involved in arachidonate metabolism, have been identified as influencing susceptibility to CAD and myocardial infarction ^[1]. Additionally, variations in the LGALS2 gene are associated with an increased risk of myocardial infarction and are involved in regulating lymphotoxin-alpha secretion ^[4].
Lipid Metabolism Genetic variants affecting lipid metabolism contribute to the risk of CAD, including through their influence on conditions like hypercholesterolemia ^[1]. Specifically, genetic variations, such as single nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene, have shown associations with CAD in research^[1].
Vascular Biology and Other Genetic Factors Genetic variants affecting vascular biology are considered plausible contributors to CAD ^[1]. A mutation in the MEF2A gene has been linked to an inherited disorder that presents features of coronary artery disease^[4]. The genetic basis for cardiac remodeling, which involves structural changes in the heart, is also an area of study in the context of cardiac health ^[9]. Furthermore, genetic variations can influence CAD risk directly or indirectly by affecting known risk factors such as hypertension and diabetes^[1].
Genomic Loci A significant genetic association for CAD has been identified on chromosome 9p21.3, with strong signals observed across a region spanning over 100 kilobases ^[1].

Pathways and Mechanisms

The development and progression of coronary artery disease involve a complex interplay of molecular and physiological mechanisms, primarily centered on the formation and instability of atherosclerotic plaques.

Genetic factors play a significant role in these processes. For instance, the genetic regulation of cellular growth and inhibition is crucial for the development of coronary artery disease and myocardial infarction. Genes such as PSRC1 (located at 1p13.3), MIA3 (at 1q41), and SMAD3 (at 15q22.33) are involved in controlling cell growth or inhibition^[7]. These cellular processes are fundamental to the formation, growth, and instability of atherosclerotic plaques ^[6].

In addition to cellular regulation, specific genetic variations are associated with the disease. Single nucleotide polymorphisms (SNPs) within the lipoprotein lipase gene have shown an association with coronary artery disease^[10]. The interleukin-18 (IL-18) system also plays a role, with genetic analysis highlighting the importance of the interleukin-18 gene in cardiovascular disease^[8].

While several genomic regions have been identified as being associated with coronary artery disease, their precise mechanisms are still being investigated. For example, associations have been found for signals on chromosomes 9p21.3, 6q25.1, and 2q36.3, but the underlying mechanisms for these connections require further clarification. Nonetheless, SNPs in a region of chromosome 9p21 have been linked to coronary heart disease^[10].

Clinical Relevance

Coronary Artery Disease (CAD) represents a significant global health burden, being a leading cause of death in many industrialized nations, including the United States^[11]. Its clinical relevance spans early identification, risk stratification, and prognostication of cardiovascular events.

Key risk factors for CAD include diabetes, hypertension, and hyperlipidemia, as well as an elevated body-mass index^[11]. A family history of CAD, particularly in parents or siblings, also contributes to an individual’s risk profile ^[11].

Several non-invasive imaging and physiological markers are crucial for assessing CAD risk and progression. The quantity of coronary artery calcium, measured by electron beam computed tomography, is a significant indicator ^[12]. Similarly, the coronary artery calcium score can predict future coronary heart disease events^[13]. Other valuable predictors include the ankle-brachial index for future cardiovascular outcomes^[14], carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke^[15], and abdominal aortic calcific deposits, which predict vascular morbidity and mortality^[16].

Diagnosis of major coronary heart disease events, such as myocardial infarction, typically relies on a combination of clinical criteria, including new Q-waves on an electrocardiogram, prolonged ischemic chest discomfort, and elevated serum biomarkers of myocardial necrosis^[11].

Ongoing research, including genome-wide association studies, continues to identify genetic variants associated with outcomes like coronary heart disease, aiming to enhance personalized risk assessment and therapeutic strategies^[11].

Frequently Asked Questions About Coronary Artery Disease

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

1. My dad had a heart attack young. Will I get heart disease too?

Yes, there’s a strong inherited component to coronary artery disease (CAD). If CAD or heart attacks cluster in your family, especially at younger ages, it suggests genetic factors might increase your susceptibility. While genetics don’t guarantee you’ll get it, they significantly influence your individual risk.

2. If I eat well and exercise, can I beat my family’s heart problems?

Absolutely, lifestyle choices play a crucial role, even with a strong family history. While genetic variations can influence your risk, good diet, regular exercise, and managing other risk factors like blood pressure and cholesterol can significantly reduce your chances of developing CAD. It’s a powerful way to counteract genetic predispositions.

3. Should I get a DNA test to check my future heart risk?

Genetic testing can provide insights into your predispositions, as specific genetic loci like the one on chromosome 9p21.3 are associated with CAD risk. However, current tests don’t give a complete picture, and many genetic factors are still being discovered. It’s best discussed with your doctor to understand its current utility for your personal situation.

4. Why do some healthy people still get heart disease?

Even with a healthy lifestyle, genetic variations can make some individuals more susceptible to coronary artery disease. These genetic factors can modulate processes like inflammation, lipid accumulation, and cellular changes in artery walls, increasing plaque formation regardless of apparent health. This highlights the complex interplay between genes and environment.

5. My cholesterol is high. Is that because of my genes?

Yes, genetics can significantly influence your cholesterol levels. Variants in genes like ABCG5 and ABCG8are critical for sterol transport and lipid metabolism, directly affecting how your body processes fats. So, even with a healthy diet, certain genetic predispositions can lead to higher cholesterol.

6. Why do heart problems run so strong in my family?

The clustering of coronary artery disease in families strongly suggests a substantial inherited component. Genetic variations can influence your risk directly or indirectly by affecting related conditions like high blood pressure, diabetes, and high cholesterol, which then contribute to CAD. This complex genetic architecture makes some families more prone.

7. Why do plaques build up in my arteries faster than others?

Your genetic makeup can influence the rate of plaque buildup. Genes play a role in biological processes like inflammation, lipid accumulation, and cellular changes within your arterial walls. Variations in these genes can make you more susceptible to the development and progression of atherosclerosis, leading to faster plaque formation.

8. Can knowing my genes really help prevent my heart attack?

Potentially, yes. Identifying your genetic predispositions offers avenues for improved overall coronary risk prediction. In the long term, this understanding can lead to more personalized screening, prevention strategies, and targeted treatments, aiming to reduce your risk more effectively than general advice.

9. Why does my doctor ask so much about my parents’ health?

Your doctor asks about family health because coronary artery disease has a significant inherited component and often clusters in families. This information helps them assess your genetic risk, which is a crucial part of your overall risk profile, even before considering your lifestyle factors. It guides personalized prevention and screening recommendations.

10. Why do some people never seem to get heart disease?

Some individuals may have protective genetic variations or a lack of risk-enhancing variants that make them less susceptible to coronary artery disease. Their genetic makeup might better regulate inflammation, lipid metabolism, or arterial health, allowing them to maintain healthy arteries even when exposed to some risk factors.

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

[1] Samani, N. J., et al. “Baseline Characteristics of Case Subjects in the WTCCC Study and the German MI Family Study.” N Engl J Med, 31 July 2009.

[2] University of Leicester et al. “A Joint Analysis of Two Genomewide Association Studies of Coronary Artery Disease.”

[3] Dawber, T. R., et al. “Epidemiological Approaches to Heart Disease: The Framingham Study.”Am J Public Health Nations Health, vol. 41, 1951, pp. 279-281.

[4] Wang, L., et al. “Mutation of MEF2A in an Inherited Disorder with Features of Coronary Artery Disease.”Science, vol. 302, 2003, pp. 1578-1581.

[5] Shiffman, D., et al. “Identification of Four Gene Variants Associated with Myocardial Infarction.” Am J Hum Genet, vol. 77, 2005, pp. 596-605.

[6] Libby, Peter, and Paul Theroux. “Pathophysiology of coronary artery disease.”Circulation, vol. 111, 2005, pp. 3481-3488.

[7] Lo, P. K., et al. “Identification of a novel mouse p53 target gene DDA3.” Oncogene, vol. 18, 1999, pp. 7765-7774.

[8] Tiret, Laurence, et al. “Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease.”Circulation, vol. 112, 2005, pp. 643-650.

[9] Ahmad, F., et al. “The genetic basis for cardiac remodeling.” Annual Review of Genomics and Human Genetics, vol. 6, 2005, pp. 185-216.

[10] Fruchart, Jean-Charles, et al. “New risk factors for atherosclerosis and patient risk assessment.”Circulation, vol. 109, suppl. I, 2004, pp. III-15–III-9.

[11] Cupples, L. Adrienne, et al. “Community-based genome-wide association study of major CVD outcomes.” N Engl J Med, 2009.

[12] Peyser, P. A., et al. “Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults.” Circulation, vol. 106, 2002, pp. 304-308.

[13] Pletcher, M. J., et al. “Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis.”Arch Intern Med, vol. 164, 2004, pp. 1285-1292.

[14] Doobay, A. V., and S. S. Anand. “Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review.”Arterioscler Thromb Vasc Biol, vol. 25, 2005, pp. 1463-1469.

[15] O’Leary, D. H., et al. “Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults.”N Engl J Med, vol. 340, 1999, pp. 14-22.

[16] Wilson, P. W., et al. “Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality.”Circulation, vol. 103, 2001, pp. 1529-1534.