Platelet genomics and the risk of atherothrombosis

Platelets play a pivotal role in atherothrombosis after coronary artery plaque rupture. The extent of response of platelets to such an event varies between individuals. This variation is for a large extent genetically controlled. A comprehensive study of sequence variation that modifies the platelet response to agonists is, however, lacking. We set out to discover the regulatory nodes of platelet function by an integrated systems biology approach. The high density genotyping of 110 genes in a cohort of more than 500 individuals, in whom the platelet response to ADP and collagen-related peptide was determined, allowed the robust definition of the first set of regulatory nodes. Microarray and proteomics studies on platelets from individuals with a so-called 'extreme end' response phenotype provided further insight into key regulators of platelet function. In addition, the completion of the HapMap project allows the comprehensive surveying of the genome for sequence variation by the testing of a limited number of single nucleotide polymorphisms (SNPs). With the advent of high density (i.e. 500,000 SNPs) genotyping arrays large number of case and control samples can be tested at an affordable cost. The recently completed Wellcome Trust Case Control Consortium (WTCCC) study has allowed us to address the question of whether common sequence variation confers risk for seven common diseases, one being myocardial infarction. The results of the WTCCC genome-wide association study and issues of case-control study design, particularly the selection of suitable controls, will be reviewed. In conclusion the integration of the results from the platelet systems biology study with those of the WTCCC project enhances our understanding of the mechanisms underlying common conditions such as atherothrombosis and provides pointers to novel cellular mechanisms and pathways.