INFLAMMATION - THE NEW TARGET FOR PREVENTION OF CORONARY ARTERY DISEASE


Robert Roberts, M.D., University of Ottawa Heart Institute, ON, Canada

New Technology that evolved in 2005 made it possible to genotype the whole human genome sequence utilizing a million DNA markers in the form of single nucleotide polymorphisms (SNPs). This led to the first genome-wide association study (GWAS) in pursuit of the genes for coronary artery disease (CAD). Since that time, the technology has evolved and with the information from the HapMap and 1000 Genomes Projects, it is possible now to genotype with over 12 million SNPs. Utilizing this technology, we first identified 9p21 risk allele for CAD, and in a collaboration with UK, USA and Germany, we have genotyped nearly 2,000 individuals. The total number of genes predisposing to CAD that have been confirmed in independent populations is 50. Analysis the data utilizing computerized metabolic pathways indicate that a major number of these genes mediate their risk through inflammation. This analysis also shows that pathways related to inflammation and those related to cholesterol interact in the pathogenesis of atherosclerosis. Comprehensive prevention of CAD will have to incorporate therapy to inhibit those selected aspects of inflammation related to the pathogenesis of CAD. Interestingly, of the 50 genes associated with increased risk for CAD, 15 are acting through known conventional risk factors and only one is directly related to myocardial infarction, the ABO locus. It is crucially important to recognize that 35 of these genes act through unknown mechanism, indicating that cholesterol is only one of many factors involved in the pathogenesis of CAD.