Journal Article

Genetic susceptibility to myocardial infarction and coronary artery disease

Eric J. Topol, Jonathan Smith, Edward F. Plow and Qing K. Wang

in Human Molecular Genetics

Volume 15, issue suppl_2, pages R117-R123
Published in print October 2006 | ISSN: 0964-6906
Published online October 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl183
Genetic susceptibility to myocardial infarction and coronary artery disease

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Atherosclerotic involvement in the coronary arteries, which can result in heart attack and sudden death, is a common disease and prototypic of a complex human trait. To understand its genomic basis, eight linkage studies of sibling pairs have been performed. Although there was limited inter-study concordance of important loci, two gene variants in the leukotriene pathway (ALOX5AP and LTA4) have emerged as susceptibility factors for myocardial infarction (MI). Genome-wide association studies have also been undertaken, and the pro-inflammatory cytokine lymphotoxin-α (LTA), and its key ligand galectin-2 (LGALS2) have been identified as genes implicated in predisposition for heart attack. By cueing into the genomic basis for low serum LDL cholesterol levels, much work has been done to advance the importance of the serine protease PCSK9, which modulates LDL receptor function. Lifelong lowered LDL cholesterol associated with PCSK9 point mutations in 2–3% of individuals have been shown to provide marked protection from coronary artery disease (CAD). Most of the success in this field has been with the phenotype of MI, which is considerably more restrictive than CAD. Four principal and interdependent processes—lipoprotein handling, endothelial integrity, arterial inflammation, and thrombosis—have been supported as important via the clustering of genes, thus far implicated in CAD susceptibility. Of note, connecting genes in a single pathway (leukotriene), of a protein and its ligand (LTAα) or from one disease to another [age-related macular degeneration (AMD); complement factor H (CFH)], or even three disease characterized by inflammation (MHC2) have now been reported. Although the population attributable risk for any of the genes identified to date is limited, such discovery is likely to be accelerated in the future.

Journal Article.  4199 words.  Illustrated.

Subjects: Genetics and Genomics

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