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  • Review Article
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Genetic susceptibility to coronary artery disease: from promise to progress

Key Points

  • Family history is a predictor of risk of coronary artery disease (CAD) even after correction for known risk factors, such as cholesterol levels and blood pressure. This indicates that unknown susceptibility genes exist, as well as those that influence these risk factors.

  • Rare Mendelian traits can cause premature CAD, often through alterations in levels of low density lipoprotein and high density lipoprotein cholesterol, but these account for a small proportion of susceptibility at the population level.

  • Mouse models have been informative for some components of atherosclerosis, but no convincing animal model exists for the crucial events that trigger myocardial infarction — that is, plaque rupture and thrombotic occlusion.

  • Data from genome-wide linkage scans indicate that although there are no genetic loci for CAD risk that have large effects, there are mappable loci with effect sizes that are comparable to those that have been successfully identified for other complex diseases.

  • Candidate-gene association studies have been plagued by poor reproducibility. Genome-wide association studies using hundreds of thousands of SNPs are now becoming feasible, and offer the best prospects for the identification of novel CAD genes.

  • Large studies are needed to provide robust proof of novel susceptibility genes in CAD because effect sizes are modest and gene–environment interactions are inevitable. However, even a gene of modest effect can be of enormous significance if it identifies a new therapeutic target or a novel biological pathway.

  • Many of the CAD-susceptibility genes that have been identified so far are involved in innate or adaptive immunity. These mirror the growing recognition of the role of inflammation in atherosclerosis and CAD and might point to new approaches for prevention and intervention.

  • Combined genetic and genomic approaches — for example, mapping of expression QTLs — show promise for studies of complex diseases. However, these approaches have still to be validated in human populations and tend to be limited to genomic analyses that are carried out on blood or blood cells, so it is not clear how informative these will be for atherosclerosis in humans.

Abstract

Family history is an important independent risk factor for coronary artery disease (CAD), and identification of susceptibility genes for this common, complex disease is a vital goal. Although there has been considerable success in identifying genetic variants that influence well-known risk factors, such as cholesterol levels, progress in unearthing novel CAD genes has been slow. However, advances are now being made through the application of large-scale, systematic, genome-wide approaches. Recent findings particularly highlight the link between CAD and inflammation and immunity, and highlight the biological insights to be gained from a genetic understanding of the world's biggest killer.

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Figure 1: Cellular processes in the development of an atherosclerotic plaque.
Figure 2: Stages in atherosclerosis and the clinical outcomes.
Figure 3: Lipid metabolism, inflammatory and thrombotic pathways that are involved in coronary artery disease.

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DATABASES

OMIM

familial combined hyperlipidaemia

familial hypercholesterolaemia

FURTHER INFORMATION

The International HapMap Project

The SNP Consortium

WHO atlas of heart disease and stroke

Glossary

Penetrance

The conditional probability that carriers of a specific genotype are affected by an inherited disease. If the penetrance is 100%, all carriers will be affected.

Low density lipoprotein (LDL) cholesterol

Circulating complexes of apolipoprotein B and cholesterol constitute LDL particles. Raised LDL cholesterol level is predictive of coronary artery disease.

Atherosclerosis

Also known as arteriosclerosis, this is a 'narrowing' or hardening of the arteries, and is a pathological process that involves the progressive expansion of lesions (plaques) that reduce blood flow in arteries.

Intermediate phenotypes

Biochemical or physiological traits that show quantitative genetic variation. These traits are thought to represent fundamental disturbances of normal cellular processes, thereby conferring risk for complex disease.

Myocardial infarction

Commonly known as heart attack. This is caused by late-stage atherosclerosis in coronary arteries, involving plaque rupture, coronary thrombosis and heart muscle necrosis.

Linkage mapping

A method for localizing genes that is based on the co-inheritance of genetic markers and phenotypes in families over several generations.

Gene-association study

An experimental design to test whether genetic markers predict the risk of developing a disease.

Quantitative trait

A biological trait that shows continuous variation (such as height) rather than falling into distinct categories (such as diabetic or healthy). The genetic basis of these traits generally involves the effects of multiple genes and gene–environment interactions. Examples of quantitative traits are body mass index, blood pressure and blood lipid levels.

Apolipoproteins

Proteins that when complexed with lipids form lipoprotein particles that are involved in the transport and metabolism of cholesterol and triglycerides.

Ischaemic stroke

A type of cerebrovascular accident that results from occlusion of cerebral arteries owing to atherosclerosis and leading to a neurological deficit or death.

High density lipoprotein (HDL) cholesterol

Cholesterol that is contained in HDL particles; it is involved in reverse cholesterol transport and is protective against coronary artery disease.

Monocytes

Circulating phagocytic white blood cells that develop into macrophages when they enter tissues.

Lymphocytes

White blood cells that are responsible for humoral and cellular immunity.

Foam cells

Macrophages that are laden with lipid (predominantly cholesterol), and that have differentiated from circulating monocytes.

Chronic stable angina

Chest pain that is experienced on exertion and results from coronary artery stenosis.

Prospective study design

An experimental design that is used in epidemiology studies. A cohort of healthy subjects are followed up over a prolonged period to determine the association of risk factors with disease.

Odds ratio

A statistical measure of the strength of a risk factor.

Pleiotropy

The phenomenon in which a single gene is responsible for several phenotypic effects.

Common disease/common variant model

A theory of causation of common, complex disease in which 'ancient' common genetic variants, some of which might have been selected for, are associated with modest disease risks.

Dyslipidaemia

Abnormality in, or abnormal levels of, lipids and lipoproteins in the blood.

Multiplex family

A family in which multiple members are affected by an inherited disease.

Angiogram

A radiological investigation that is used to clinically evaluate the severity of coronary atherosclerosis.

LOD score

The base 10 logarithm of a likelihood ratio statistic; this is a preferred statistic for linkage analysis that indicates the strength of linkage.

Microsatellites

Short (2–5 nucleotides) direct sequence repeats, which are often highly polymorphic and are therefore useful markers in linkage analysis.

Leukotrienes

Regulators of allergic and inflammatory reactions that are produced from arachidonic acid by the lipoxygenase pathway in white blood cells.

Genetic drift

The (stochastic) change in frequency of genetic markers across generations.

Population stratification

Populations that are composed of subgroups with different ancestries. If the frequency of disease varies across the subpopulations then spurious (false-positive) gene associations can be detected.

Linkage disequilibrium

The non-random association of tightly linked genetic markers, or of genetic markers with disease.

Neutrophils

White blood cells that are involved in chemotaxis and phagocytosis.

Macrophages

Mononuclear phagocytic cells that are found in tissues; they are derived from circulating monocytes.

Lipopolysaccharide

(Also known as endotoxin.) A molecule with lipid and complex sugar moieties that is used by gram-negative bacteria to evade host immune defences.

Metabolic syndrome

The occurrence of hyperinsulinaemia, glucose intolerance, dyslipidaemia, hypertension and obesity in an individual.

Pathogen-associated molecular patterns

Molecules shared by multiple prokaryotic pathogens that are relatively invariant (for example, lipopolysaccharide and flagellin).

NF-κB pathway

The signal transduction pathway that is triggered by the inducible nuclear transcription factor NF-κB. It has a central role in immunological processes.

Carotid artery

The large artery in the neck that carries blood from the heart to the brain.

Acute coronary syndrome

A group of clinical symptoms that is associated with acute myocardial ischaemia following plaque rupture.

Coronary artery stenosis

The chronic narrowing of the coronary artery lumen.

TNF ligand family

Tumour necrosis factors are pro-inflammatory cytokines; the superfamily of TNF ligands have a wide range of functions, including apoptosis, B-cell and T-cell co-stimulation, and bone metabolism.

Aortic sinus

One of the anatomical dilations of the ascending aorta (the main artery that carries blood from the heart to the body), which occurs at the aortic root, just above the aortic valve.

Two-hybrid system

An experimental approach that is used to clone genes for which the protein products interact with another protein of interest.

Phage display

An experimental cloning system in which proteins are displayed on the surface of bacteriophages after fusion with coat proteins to allow the identification of novel protein interactions.

Lectin

A molecule with multiple sugar-binding sites that agglutinates cells.

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Watkins, H., Farrall, M. Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev Genet 7, 163–173 (2006). https://doi.org/10.1038/nrg1805

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