Modelli poligenici e predizione del rischio cardiovascolare

The genetic basis of coronary artery disease (CAD) has been well demonstrated and the relative scientific knowledge is progressively growing and refining, also by means of powerful technological tools and supports, like those that allowed the performance of the so-called “genomewide association” studies. Nevertheless, we have not yet yielded an effective translation of the stimulating results of molecular biology and genetics into the real clinical practice. More stringently, we have to keep in mind that the multifactorial and multistep pathogenesis of CAD implies by itself that, in general, a single genetic variant can confer at best only a modest risk, with a very limited impact in assessing individual’s risk of CAD. To overcome this limitation, polygenic models, i.e. strategies evaluating simultaneously the effect of multiples alleles for determining the risk of disease, are rapidly becoming popular. The rational leading of all polygenic models is substantially represented by the hypothesis, biologically plausible, that the simultaneous presence of several genetic variations with modest but defined effects on disease susceptibility could influence the risk of disease in a given subject in a clinically significant manner. The three studies presented in this thesis show possible applications of polygenic models in the prediction of cardiovascular risk. At this time, certainly, polygenic models are still imperfect and need to be further elaborated and improved under several points of view, from the selection of the genetic variants to the mathematical models used to assess their combined effects. Nonetheless, polygenic models emphasize the importance of having a holistic approach to complex diseases, like CAD, taking into account the significant limitations related to a partial vision.