Genetic risk factors of stroke - The Vienna stroke data bank

Research project P 13902 Genetic ristk factors of stroke - The Vienna Stroke Data Bank Wolfgang LALOUSCHEK 11.10.1999 In addition to well-known risk factors like arterial hypertension or hypercholesterolemia also hereditary components play a role for the manifestation of vascular disease, including stroke. Several hereditary diseases which are accompanied by extremely early and numerous vascular complications are known, but these are very rare. Recently, several mutations and polymorphisms have been described which are highly prevalent in the population, and which may be associated with an increased risk of vascular disease. These are: A. The thrombomodulin C1418T dimorphism; B. The plasminogen-activatorinhibitor 4G/5G polymorphism; C. The glycoprotein IIb/IIIa P1A2 polymorphism; D. The factor V Leiden mutation and E. The prothrombin G20210A mutation. These genetic variations, each of which affects components of the coagulation system, have recently been suspected as candidate genetic risk factors of arterial vascular disease (A., B., C.) and/or venous thrombosis (D., E.). However, with respect to the possible role of these mutations and polymorphisms in the etiology of stroke there exist no (A., B.) or conflicting (C., D. E.) data. The present project is designed to investigate these mutations in patients with the diagnosis of stroke/TIA and control subjects without clinically manifest vascular disease. The study will be performed within the Vienna Stroke Data Bank which is a multicenter, hospital-based stroke data bank project. Within the Vienna Stroke Data Bank all patients with the clinical diagnosis stroke/TIA who are admitted to one of the neurological departments of Vienna within 72 hours of symptom-onset will be included. In addition to a detailed medical history and repeated, standardized neurological examinations, also the results of technical investigations (cranial computed tomography, ultrasound examination of the cervical vessels, etc.) and laboratory data will be systematically documented. The follow-up period will be two years, including repeated neurological examinations. 1500 patients and an equivalent number of age- and sex matched control subjects without clinically manifest vascular disease shall be recruited over a period of two years. The investigation of genetic risk factors in material collected from individuals who are documented within a stroke data bank gives the opportunity to gain insights which can only be obtained in such a setting. Not only will it be possible to investigate the prevalence of the mutations and polymorphisms in a considerable number of patients and control subjects, but, even more important, the clinical features of these patients will be systematically and uniformly documented and can readily be combined with the genetic information. As a consequence, genetic analyses can be focuses on specific subgroups of patients with a high likelihood of a genetically determined disposition to cerebrovascular disease. These groups comprise patients without major conventional risk factors of stroke (e.g. hypertension, diabetes mellitus, or cigarette smoking), patients below an age of 60 years, or patients with a positive family history of vascular disease in two or more relatives. Specific interest will be drawn on possible effects of the combined occurrence of two or more of the investigated mutations in an individual. Furthermore, family studies are planned in defined patients. Finally, possible correlations of the mutations with the type or severity of the event as well as with short-term- and long-term-outcome can be analyzed. Early knowledge of a disposition to vascular disease, including stroke, can finally help to direct specific prophylactic interventions in order to prevent the occurrence of cerebrovascular events.

Besides the established vascular risk factors, genetic factors influence the risk of vascular diseases, including stroke. Recently, several mutations and polymorphisms were described which may be associated an increased vascular risk. These are: the factor V Leiden mutation; the prothrombin G20210A mutation, the MTHFR C677G polymorphism, the PAI 4G/5G polymorphism, the Factor XIII Val34Leu mutation, the interleukin-6 G(-174)C polymorphism and the P-Selectin Thr715Pro polymorphism. These genetic variations influence the coagulation system or the inflammation system and have been associated with an increased risk of arterial or venous vascular events. Data with respect to the influence of these variations on the risk of stroke is missing or equivocal. In the present project, the prevalence of these mutations in patients with ischemic stroke or transient ischemic attacks and control subjects without clinically manifest vascular disease was analysed. The project was carried out within the Vienna Stroke Registry (VSR), which is a multicenter, hospital-based stroke registry. A detailed medical history, standardized neurological examinations at defined intervals, and the results of technical and laboratory investigations are documented. Die genetic variations were analysed in 1000 patients with stroke/TIA and in an equivalent number of control subjects. The Factor V Leiden mutation was present in 6.6% of the patients and in 7.1% of the control subjects, a non- significant difference. Therefore the Factor V Leiden Mutation does not seem to represent a risk factor for stroke in the general population. However, in the subgroup of women below 60 years the mutation was present in 15.5% of the smoking and only in 4.2% of the non-smoking patients (p=0.027). In patients who took oral contraceptives at the time when the stroke occurred, the mutation was present in 18.2%. There was a tendency towards a higher prevalence of the mutation in younger, smoking female patients, which was even higher in patients who additionally took oral contraceptives (25%). Due to small numbers in these subgroups these results were not significant, but indicate for the first time, that the Factor V Leiden Mutation might be associated with an increased risk of stroke in smoking women who take oral contraceptives. Further studies in specific populations are underway to clarify this question. The prothrombin G20210A mutation was significantly more prevalent in male patients than in the control subjects (6,5% vs. 1,1%; OR=5.5 (1.8-16.9). The PAI 4G/5G polymorphism was somewhat more prevalent in male smoking patients. With respect to the Factor XIII Val34Leu Mutation and the C677T MTHFR mutation we found no difference between patients with ischemic stroke, intracerebral hemorrhage and control subjects. We found that homozygous carriers of the interleukin-6 174 G-genotype had a worse outcome than patients with the other genotypes. We found a higher prevalence of the P-Selectin Thr715Pro Polymorphismus in patients than in control subjects. Our results show, that some of the investigated genetic variations exhibit an influence on the risk of stroke, at least in certain subgroups of patients or in interaction with other vascular risk factors. We also found evidence for a genetic influence on the course of acute stroke. A better understanding of the genetic influence on stroke risk and outcome will enable us to develop more specific preventive measures and new therapeutic strategies in the future..