Genetic variants in an endothelial cell membrane protein (thrombomodulin) participating in the protein C pathway : clinical studies of heart disease and in vitro analysis

• Main Author: Konstantoulas, Constantine James
• Published: University College London (University of London) 2006
• Subjects: 616.12042
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429284

Thrombin is the key enzyme in the formation of a fibrin clot. Control of its activity and generation forms an important haemostatic function preventing occlusive blood clot formation. Deregulation of this control process results in increased thrombin generation and thus increased clot formation in thrombotic conditions. Thrombomodulin (Tm) is an important thrombin-regulatory gene expressed at the endothelial cell surface, and as such may have a role in modifying susceptibility to occlusive thrombotic disease. This thesis focuses on the role of gene variants, within Tm, in determining risk of coronary heart disease (CHD). Contribution to risk of CHD by variants in the Tm gene was assessed in a case-control study (H1FMECH), a large prospective study of heart disease (NPHSII) and a cross sectional study of type 2 diabetes (EDSC). Tm gene variant interaction with clinical and plasma markers of CHD was also studied. The consequences of Tm gene variants upon thrombin generation and inflammation were also addressed. Tm antigen levels and cofactor activity for protein C (PC) activation were assessed to determine whether the overall contribution to heart disease by dysfunctional variants could be estimated. In vitro functional studies were performed, to determine the molecular mechanisms of the effect of the variants showing strong effects on risk and to further our understanding of the role of Tm in the pathogenesis of CHD. The work included in this thesis demonstrates that genetic variation in the Tm gene may influence risk for CHD in an environment of metabolic syndrome. It adds to a growing body of evidence suggesting a contribution to CHD risk caused by variants or mutations in the Tm gene.