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-alpha (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 (LTAalpha) 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.