Prothrombotic gene variation and cerebral ischaemia of arterial origin

Stroke is the second most common cause of death and a leading cause of adult disability worldwide. Ischaemia is the cause in about 80% of all strokes. Atherosclerotic lesions in the cerebropetal and intracranial arteries lead to cerebral ischaemia of arterial origin. Cerebral ischaemia and atherosclerosis have a genetic basis. Genetic factors may help to identify stroke patients at high risk for new events. We studied associations between prothrombotic gene variation and cerebral ischaemia of arterial origin. Chapter 3 is a cohort study among 887 patients with cerebral ischaemia. During a 4.6-year mean follow-up period new vascular events occurred in 135 patients. None of 22 selected prothrombotic variants was associated with the occurrence of new vascular events. This study does not support the use of prothrombotic gene variants to identify stroke patients at increased risk for new vascular events. Chapter 4 is a case-control study in 316 long-term survivors (cases) and 887 patients with recent cerebral ischaemia (controls). Only two of 23 prothrombotic variants were associated with reduced survival after stroke. These variants do not appear to play an important role in survival after cerebral ischemia. In Chapter 5 we studied the effect of prothrombotic gene variation on atherosclerosis in 689 patients with nondisabling cerebral ischaemia. None of 22 prothrombotic variants was associated with carotid intima-media thickness or age. Only one variant was associated with symptomatic carotid stenosis. Prothrombotic gene variation does not seem to affect the pathogenesis of atherosclerosis. In Chapter 6 we compared genotype frequencies between 621 stroke patients with large vessel disease (LVD) and 266 patients with small vessel disease (SVD). Only one of 22 variants was not equally prevalent among LVD and SVD patients. Prothrombotic gene variants may not be specific for one stroke subtype. Claims about genetic associations with specific subtypes should be interpreted with caution. In Chapter 7 we found the carotid intima-media thickness to be larger in patients with LVD than in those with SVD. Carotid intima-media thickness is an established marker of artherosclerosis. This supports the hypothesis that LVD and SVD have a different pathogenesis. Chapter 8 is a case-control study among 190 young women with ischaemic stroke and 767 women without cardiovascular disease. The Phenylalanine allele of the Tyr204Phe variant conferred a 9-fold increased risk of stroke. The combination of oral contraceptive use and carriership of the 204Phe allele led to a 20-fold increase in stroke risk. TheTyr204Phe variant of the coagulation factor XIII subunit A gene constitutes a strong and common genetic factor for ischaemic stroke in young women. Genetic screening preceding oral contraceptive use is not warranted because of the low incidence of ischaemic stroke among young women. Chapter 9 is a nested case-control study in patients with cerebral ischaemia on oral anticoagulant treatment. A variant in the alpha fibrinogen gene was associated with a decreased anticoagulant-related bleeding risk and factor V Leiden conferred an increased bleeding risk. If replicated, these findings may have implications for the future selection of patients for oral anticoagulant treatment.