Genetic susceptibility to myocardial infarction and coronary artery disease
1 Department of Genetics and 2 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, BRB 724, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA and 3 Department of Cell Biology, 4 Department of Molecular Cardiology and 5 Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH, USA
* To whom correspondence should be addressed. Tel: +1 216 368 4943; Fax: +1 216 368 0491; Email: eric.topol{at}case.edu
Received May 26, 2006; Accepted July 12, 2006
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-
(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 (LTA) 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.
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