GENETIC REGULATION OF INFLAMMATION-MEDIATED HAEMOSTASIS ACTIVATION: A FAMILY-BASED APPROACH

Myocardial infarction (MI) is due to a combination of genetic and environmental factors. The last decade has brought new molecular strategies which may help understanding the pathogenic mechanisms of the disease. However, at present, there are not firmly established genetic markers which could be utilised to identify high-risk populations. Activation of haemostasis, that constitutes the basis of thrombus formation, is the final step of a cascade of events in which genetic alterations can be determinant. Increase in inflammatory mediators has been implicated as a triggering factor. Interleukin 1- (IL1-) stimulates the synthesis of other inflammatory mediators and of haemostatic factors. It also stimulates interactions among cells and their consequent activation. This entire pathway is genetically regulated, and first evidences from association studies indicate a role of some IL1- polymorphisms in regulating both IL1- release and premature MI in association studies. However, such studies can suffer from epidemiological weaknesses, and family-based linkage studies are needed to confirm results. Among proposed approaches, the variance component (VC) method has been demonstrated to have good power to map genes influencing complex traits (as MI), especially investigating quantitative traits. The present project is aimed at identifying genes involved in the pathway inflammation-haemostasis-MI by using VC method. Data will come from large pedigrees selected through probands with MI before the age of 45. In addition, new high throughput genotyping techniques will be developed that allow to study multiple genes in large