Role of P2RY12 gene variants and biological variation in arterial thrombosis

Arterial thrombosis is the leading cause of morbidity and mortality in the Western world. Plaque rupture induces arterial thrombus formation, which may result in vascular occlusion. Depending on the localization of the occluded vessel, arterial thrombosis can affect the cardiovascular, cerebrovascular and peripheral arterial systems with clinical manifestations such as myocardial infarction and ischemic stroke. Arterial thrombosis is a multifactorial disease, and both genetic and environmental factors are known to contribute to its pathogenesis. In this thesis we have focused on the role of these genetic factors with an emphasis on common variation in the platelet receptor P2RY12 gene. The P2Y12 receptor plays a central role in platelet aggregation and is the pharmacologic target of widely prescribed antiplatelet drug clopidogrel (Plavix). Studies described in Part I have shown that common variation in the P2RY12 gene are a risk factor for arterial thrombosis at young age. In addition, we have shown that these genetic variations are a significant determinant of the on-clopidogrel platelet reactivity and the pharmacodynamic response to cangrelor, an alternative P2Y12 receptor antagonist. In another study we report that the com! mon variation in the P2RY12 gene is associated with the risk of restenosis within 1 year after percutaneous coronary interventions. In Part II, the biological variation of several hemostatic and inflammatory factors important in arterial thrombosis is described. In addition, we report an association between the concentrations of air pollution and a part of this biological variation, which may provide an explanation for the relationship between air pollution and cardiovascular disease.

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