CORDIS - EU research results

Genetic regulation of the end-stage clotting process that leads to thrombotic stroke

Final Report Summary - EUROCLOT (Genetic regulation of the end-stage clotting process that leads to thrombotic stroke)

Thrombotic stroke is a disabling condition, affecting an estimated 650 000 Europeans annually, with considerable mortality and costing over EUR 30 billion per year. Genetic factors account for a substantial component of the incidence and mortality of stroke. There is little effective therapy. The project aimed to identify and validate potentially therapeutically useful genes associated with thrombotic stroke using a novel approach. Stroke is a complex end-point disease involving the interaction of many pathologic processes, such as vessel wall atheroma, hypertension, platelet function and coagulation. The project focused on uncovering the genes that control the end-stage of the coagulation process that leads directly to the production of the thrombus (clot) that causes vascular obstruction and tissue death. Clinical studies indicate that alterations in fibrin structure and / or function create a prothrombotic phenotype, which increases vascular risk. Twin studies have shown a substantial genetic component to levels of activation peptides and the final common pathway of thrombus (fibrin structure / function).

The aim of EUROCLOT was to identify the major genes involved in variations of the end-stage clotting process and investigate the role of these novel genes (and existing candidate genes) in the pathogenesis of stroke across Europe. EUROCLOT would study stroke intermediate phenotypes in over 3 000 twins from GenomEUtwin project involving 8 countries and 700 subjects from extended families from the GAIT2 (Spain) and EuroHead (Finland) studies. Genes would be validated in 1 000 stroke cases including those from the large European prospective MORGAM study. Cross-European differences in allelic frequencies would be examined along with their relative impacts. Phenotyping would be standardised and harmonised and a European database established.

Progress of the project overall has been satisfactory with all of the deliverables have been met. Gene-environment interactions were explored using linear regression of the replicated loci for variations with the major environmental factors - smoking, BMI and fasting insulin and glucose levels - and no clear significant interactions were found. This study was, however, not sufficiently powered to observe small to moderate gene-environment interactions, given the modest effect sizes of the genetic risk factors found in GWA studies and no major gene-environment interaction was detected.