From intracranial aneurysm to subarachnoid hemorrhage : unraveling the genetics

Abstract

The principle aim of this thesis was to identify genes involved in intracranial aneurysms and subsequent aneurysmal subarachnoid hemorrhage (SAH) especially those implicated in the maintenance of the integrity of the extracellular matrix (ECM) of the arterial wall. These genes were identified using a study population with a familial preponderance of the disease. In part 1 of the thesis this study population and its familial risk factor were described. The population attributable risks of the known risk factors for aneurysmal SAH were outlined. Characteristics of intracranial aneurysms (i.e. size and number) in patients with a familial form of aneurysmal SAH and those with the non-familial or sporadic form were compared. Familial aneurysms appeared generally larger at time of rupture and more often multiple than non-familial or sporadic aneurysms. Demographic and clinical features in patients of families with familial intracranial aneurysms and different patterns of inheritance were compared and no differences were found. In addition, the ages of patients with SAH in affected parent-child pairs were compared and the age at time of SAH in parents was significantly higher than in their children. Finally, subtle manifestations of connective tissue or the ECM disease between patients with aneurysmal SAH and controls were compared to assess whether intracranial aneurysms is not a localized disruption but may rather represent a more general laxity of the connective tissue and ECM. Patients with ruptured intracranial aneurysms had a higher degree of joint mobility compared to controls. Part 2 described the identification of genes, especially those implicated in the maintenance of the integrity of the ECM of the arterial wall, involved in the occurrence of intracranial aneurysms and aneurysmal SAH. Allelic association with intracranial aneurysms was demonstrated for several functional and positional candidate genes of the ECM: versican (CSPG2), serpine1 (PAI1), perlecan (HSPG2), fibrillin (FBN2) and collagen 4A1 (COL4A1). A genome-wide linkage study was performed in a large Dutch family with intracranial aneurysms and linkage was shown to a locus on chromosome 1 and on chromosome X. A literature study describing and comparing the genomic loci identified in whole genome linkage studies on intracranial, thoracic and abdominal aortic aneurysms in search of possible common genetic risk factors for the three types of aneurysms, showed five chromosomal regions that may play a role in the pathogenesis of two or more aneurysmal types. Part 3 explored the utilization of genetic factors in clinical studies on aneurysmal SAH. The insulin-like growth factor-1 (IGF-1) and the tumor necrosis factor-A (TNF-A) genes that are expressed after ischemia and that influence recovery after ischemia in the animal model of ischemia appeared associated with outcome in patients after aneurysmal SAH. Analyzing factors involved in the occurrence of rebleeding and secondary cerebral ischemia after aneurysmal SAH no association of genes modifying coagulation with risk of secondary cerebral ischemia and rebleeding after aneurysmal SAH could be demonstrated.