Genomics of coronary artery disease and myocardial infarction. From Genome Wide Association Studies to the Next-Generation-Sequencing era

The importance of a positive family history for coronary artery disease (CAD) or myocardial infarction (MI) is a long-known notion to any practicing physician. However, as for any complex disease, our understanding of the genetic basis of CAD/MI has proven very difficult. The scenario has recently changed with the advent of genomic techniques able to obtain high-throughput unbiased information on the whole genome, at variance with traditional genetic studies focusing on single or few candidate genes. The Genome Wide Association Studies (GWAS) have revealed near sixty genetic loci significantly associated with CAD/MI. While the GWAS have undoubtedly represented a major breakthrough in CAD/ MI genomics, suggesting new pathways (i.e. that driven by the 9p21.3 locus) and challenging some dogmas from observational epidemiology (i.e. downsizing of the causal role of HDL-cholesterol levels), they have explained only a fraction of CAD/MI heritability. The complementary application of the so-called Next Generation Sequencing (NGS) technologies is rapidly adding new information to solve the puzzle on CAD/MI “missing heritability”. At present, a bottleneck is represented by our capability to interpret correctly sequencing data. This will require a strongest integration among molecular biologists, epidemiologists, statisticians, and, in particular, clinicians.