A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in ... A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. Gunel and Lifton (1996) noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. Bersano et al. (2008) reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; 612309), the renin-angiotensin-aldosterone system (see, e.g., ACE; 106180), homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism (see, e.g., APOE; 107741). See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519).
Zee et al. (2004) collected DNA samples at baseline in a prospective cohort of 14,916 initially healthy American men. The authors then genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and ... Zee et al. (2004) collected DNA samples at baseline in a prospective cohort of 14,916 initially healthy American men. The authors then genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2,092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. Two polymorphisms related to inflammation, val640-to-leu in the SELP gene (173610.0002) and a 582C-T transition in the IL4 gene (147780), were found to be independent predictors of thromboembolic stroke (odds ratio of 1.63, P = 0.001, and odds ratio of 1.40, P = 0.003, respectively). Casas et al. (2004) performed a comprehensive metaanalysis of 120 case-control studies of genetic associations in ischemic stroke in white adults and determined the pooled odds ratios (OR) conferred by specific genetic changes. Statistically significant associations were identified for 4 polymorphisms: factor V Leiden (R506Q; 612309.0001, OR of 1.33); methylenetetrahydrofolate reductase (A222V; 607093.0003, OR of 1.24); prothrombin (20210G-A; 176930.0009, OR of 1.44); and angiotensin-converting enzyme (insertion/deletion, OR of 1.21). These were also the most investigated candidate genes, including 4,588, 3,387, 3,028, and 2,990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes: factor VIII (300841), apolipoprotein E (107741), and human platelet antigen type 1 (173470). Casas et al. (2004) concluded that although there is no single gene with a major effect, common variants in several genes contribute to the risk of stroke. In a genomewide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction (608557), Helgadottir et al. (2004) found suggestive linkage to chromosome 13q12-q13. By analysis of a candidate gene in the region, ALOX5AP (603700), they identified a 4-SNP haplotype, 'HapA' (defined by SG13S25, SG13S114, SG13S89, and SG13S32), that conferred a nearly 2 times greater risk of myocardial infarction and stroke. Another 4-SNP haplotype, 'HapB', was associated only with myocardial infarction. To assess further the contribution of the ALOX5AP variants HapA and HapB in a population outside Iceland, Helgadottir et al. (2005) genotyped 7 SNPs that defined both of these haplotypes from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The haplotype that was at-risk in Iceland, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36 under the assumption of a multiplicative model (p = 0.007). They did not detect association between HapB and ischemic stroke in the Scottish cohort. However, HapB was overrepresented in male patients. Fornage et al. (2005) genotyped 12 SNPs in the EPHX2 gene (132811) in 315 stroke patients and 1,021 controls from the ARIC study and identified 2 common EPHX2 haplotypes that were associated with increased and decreased risk of ischemic stroke in African Americans (adjusted p less than 0.04). In whites, 2 different common haplotypes showed suggestive evidence for association with ischemic stroke risk but, as in African Americans, these relationships were in opposite direction. Fornage et al. (2005) suggested that multiple variants may exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence. In large studies in Japan, Kubo et al. (2007) demonstrated association between cerebral infarction (ischemic stroke) and a nonsynonymous SNP in the PRKCH gene (V374I; 605437.0001), which caused enhancement of PKC activity in transfected 293T cells. Furthermore, Kubo et al. (2007) found that PKC-eta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. These results supported a role for PRKCH in the pathogenesis of cerebral infarction. Berger et al. (2007) performed 2 large case-control studies involving 1,901 hospitalized stroke patients and 1,747 regional population controls and found that the E298D polymorphism of the NOS3 gene (153729.0001) was significantly associated with ischemic stroke independent of age, gender, hypertension, diabetes, and hypercholesterolemia. Zacho et al. (2008) studied 10,276 persons from a general population cohort, including 1,786 in whom ischemic heart disease developed (see 607339) and 741 in whom ischemic cerebrovascular disease developed, and an additional 31,992 persons from a cross-sectional general population study, of whom 2,521 had ischemic heart disease and 1,483 had ischemic cerebrovascular disease. Finally, Zacho et al. (2008) compared 2,238 patients with ischemic heart disease with 4,474 control subjects and 612 patients with ischemic cerebrovascular disease with 1,224 control subjects. Zacho et al. (2008) measured levels of high-sensitivity C-reactive protein (CRP: 123260) and conducted genotyping for 4 CRP polymorphisms and 2 apolipoprotein E polymorphisms (dbSNP rs429358 and dbSNP rs7412). The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the 4 CRP polymorphisms dbSNP rs1205, dbSNP 1130864, dbSNP rs3091244, and dbSNP rs3093077 were associated with an increase in CRP levels up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, Zacho et al. (2008) found that apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk of ischemic heart disease. Zacho et al. (2008) concluded that polymorphisms in the CRP gene are associated with marked increases in CRP levels, but that these are not in themselves associated with an increased risk of ischemic vascular disease.