Stroke, Ischemic

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2019-09-22

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A number sign (#) is used with this entry because common variants in several genes have been associated with increased susceptibility to development of ischemic stroke (see MOLECULAR GENETICS).

A locus for susceptibility to ischemic stroke has been mapped to chromosome 5q12 (STRK1; 606799).

Several conditions in which stroke occurs are inherited in a classic mendelian pattern. As reviewed by Tournier-Lasserve (2002), these monogenic disorders have a low prevalence but a high risk for stroke in mutation carriers. The genes that have been identified include APP (104760), BRI (603904), and CST3 (604312), causing autosomal dominant amyloid angiopathies; NOTCH3 (600276), causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310); and KRIT1 (604214), causing cavernous angioma (116860).

Description

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).

Other Features

Among 512 Korean patients with ischemic stroke, Bang et al. (2005) found a significant association between intracranial atherosclerotic stroke (143 patients) and components of the metabolic syndrome (AOMS1; 605552), compared to those with extracranial atherosclerotic stroke (77 patients) and those with nonatherosclerotic stroke (292 patients). The association was particularly strong with regard to hypertension, abdominal obesity, and HDL cholesterol levels.

Campbell et al. (2006) found that increased serum levels of soluble vascular adhesion molecule-1 (VCAM1; 192225) predicted recurrent ischemic stroke in a study of 252 patients. A smaller but similar trend was noted for serum levels of N-terminal pro-B-type natriuretic peptide (NPPB; 600295). Patients in the highest quarters for both sVCAM1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared to patients in the lowest quarters for both biologic markers.

Among 195 nondemented stroke survivors over age 75 years who were followed for 2 years for cognitive decline and 5 years for survival, Martin-Ruiz et al. (2006) found that longer telomeres in peripheral blood mononuclear cells (see 609113) was associated with decreased risk for death (p = 0.04) and dementia (p = 0.002) and with a smaller reduction in Mini-Mental State Examination score (p = 0.04). The authors suggested that peripheral leukocyte telomere length may serve as a biomarker for long-term stroke outcomes.

Inheritance

Genetic Factors

Ischemic stroke is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors, and can therefore be viewed as a paradigm for late-onset, complex polygenic diseases (see Dominiczak and McBride, 2003).

Several lines of evidence support a role for genetic factors in the pathogenesis of stroke. These include studies of twins (Brass et al., 1992) and familial aggregation (Brass and Shaker, 1991). Both environmental and genetic risk factors for ischemic stroke have been well characterized (Sacco et al., 1997). Chief among these are age (the single most important risk factor), hypertension, cardiac disease, sickle cell disease, and hyperhomocysteinemia. Intimal-medial thickness of the common and internal carotid arteries is strongly correlated with cerebrovascular accidents. Duggirala et al. (1996) demonstrated high heritability, with 66 to 74.9% of the total variation being accounted for by genetic factors and the remainder being attributable to covariates such as lipids, diabetes, blood pressure, and smoking.

Catto (2001) reviewed evidence that stroke has a genetic basis and that the hemostatic system is an important risk factor for stroke. He evaluated the genetic regulation of a number of these hemostatic proteins.

Pathogenesis

Ischemic strokes can be further subdivided into large vessel strokes and those resulting from the occlusion of small intracerebral vessels. The majority of large vessel ischemic strokes are caused by thromboemboli arising from the carotid artery, aortic arch, or heart (Delanty and Vaughan, 1997). Small vessel strokes are associated with lipohyalinosis of small intracranial blood vessels observed as lacunae and leukoaraiosis on magnetic resonances imaging of the brain. Lacunar infarctions are associated with diabetes mellitus, hypertension, and disorders such as CADASIL (Pantoni and Garcia, 1997).

Hypertension

The importance of hypertension in stroke pathogenesis has conclusively been shown by large randomized prospective trials, demonstrating that treatment of hypertension reduces the risk of stroke by at least 40% (MacMahon et al., 1990). Hypertension not only accelerates atherosclerosis in the large arteries but also affects smaller penetrating arteries of the brain by a process known as lipohyalinosis or fibrinoid necrosis. This process weakens the vessel wall, and extravasation of blood through the disintegrating wall follows. Ultimately, this results either in thrombosis or in rupture of the vessel wall. Gunel and Lifton (1996) stated that not all hypertensive individuals develop lipohyalinosis, and lipohyalinosis has also been reported in normotensive individuals. These observations raise the possibility that genetic predisposition may be important in the pathogenesis of stroke. Such predisposition may include not only genes contributing to elevated blood pressure but also genes acting independently of blood pressure.

Mapping

See ATFB5 (611494) for discussion of an association between SNPs at chromosome 4q25 and the cardioembolic subtype of ischemic stroke.

Associations Pending Confirmation

In a genomewide association study of 4 large cohorts including 19,602 Caucasians in whom 1,544 incident strokes (1,164 ischemic strokes) developed over an average follow-up of 11 years, Ikram et al. (2009) found linkage to rs11833579 and rs12425791 on chromosome 12p13 near or within the NINJ2 gene (607297). Both SNPs showed significant associations with total stroke (p = 4.8 x 10(-9) and p = 1.5 x 10(-8), respectively) and ischemic stroke (p = 2.3 x 10(-10) and p = 2.6 x 10(-9), respectively). A significant association with rs12425791 was replicated in 3 additional cohorts, yielding an overall hazard ratio of 1.29 (p = 1.1 x 10(-9)). However, the International Stroke Genetics Consortium and Wellcome Trust Case-Control Consortium 2 (2010) failed to replicate an association between ischemic stroke and the variants rs11833579 and rs12425791 on 12p13 in a combined sample of 8,637 cases and 8,733 controls of European ancestry, as well as in a population-based genomewide cohort study of 278 ischemic strokes among 22,054 participants.

Matsushita et al. (2010) specifically examined the association of rs11833579 and rs12425791 with ischemic stroke in a case-control study of 3,784 Japanese patients and 3,102 Japanese controls. After adjustment for age and cardiovascular risk factors, rs12425791 was significantly associated with atherothrombotic stroke (p = 0.0084; odds ratio of 1.15) in the total cohort. However, after sex stratification, the association was no longer significant for males (p = 0.086) and showed only a weak association with females (p = 0.027). There was no association between stroke and rs11833579 in any of the comparisons.

Matsushita et al. (2010) performed a large case-control association study and a replication study in a total of 2,775 cases with atherothrombotic stroke and 2,839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, the SNP rs2280887 in ARHGEF10 (608136) was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test. The association was replicated in an independent set of 1,915 cases and 1,979 controls. Subsequent fine mapping found another 3 SNPs that showed similar association due to strong linkage disequilibrium to rs2280887. In the functional analyses of these 4 highly associated SNPs, rs4376531 affected ARHGEF10 transcriptional activity due to a difference in SP1 (189906)-binding affinity. In a small GTPase activity assay, the gene product of ARHGEF10 specifically activated RHOA (165390). A population-based cohort study revealed that subjects with rs4376531 CC or CG had an increased incidence of ischemic stroke (P = 0.033). The authors suggested that the functional SNP of ARHGEF10 confers susceptibility to atherothrombotic stroke.

Chen et al. (2010) identified a single-nucleotide polymorphism (SNP), rs2507800, within the 3-prime untranslated region (UTR) of angiopoietin-1 (ANGPT1; 601667) that influences regulation of angiopoietin-1 by miR211 (613753). The A allele of rs2507800, but not the T allele, suppressed angiopoietin-1 translation by facilitating miR211 binding. Subjects carrying the TT genotype had higher plasma angiopoietin-1 levels than those with the A allele. The association of the variant with stroke was tested in 438 stroke patients and 890 controls, and replicated in an independent population of 1791 stroke patients and 1843 controls. The TT genotype resulted in a significant reduction in overall stroke risk (p = 0.0003), ischemic stroke (p = 0.007) and hemorrhagic stroke (p = 0.007). These results were confirmed in an independent study. The authors concluded that the TT genotype of rs2507800 in the 3-prime UTR of angiopoietin-1 might reduce the risk of stroke by interfering with miR211 binding.

Molecular Genetics

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 (163729.0001) 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 (rs429358 and 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 rs1205, 1130864, rs3091244, and 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.

Animal Model

Rubattu et al. (1996) reported the chromosomal mapping of quantitative trait loci (QTLs) contributing to stroke in a rat model of this complex disorder of multifactorial and polygenic etiology. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, they mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genomewide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder), segregated. They identified 3 major QTLs: STR1, STR2, and STR3, with lod scores of 7.4, 4.7, and 3.0, respectively. These 3 QTLs accounted for 28% of the overall phenotypic variants. STR1 mapped to rat chromosome 1 and strongly affected latency to stroke in a recessive mode, accounting for 17.3% of overall phenotypic variants in the cross studied. Additional consideration of age-adjusted blood pressure values as a covariate had no effects on the resultant statistic, indicating to Rubattu et al. (1996) that this locus acts independently of blood pressure. STR2, on the other hand, conferred a significant protective effect against stroke in the presence of SHRSP alleles. STR2 accounted for 9.6% of overall variants in stroke latency. The peak protective effect mapped close to the gene coding for atrial natriuretic factor (ANF; 108780) on rat chromosome 5. In the rat, as in man and mouse, the gene for brain natriuretic factor, BNF, colocalizes with ANF. STR3, a locus linked to rat chromosome 4, conferred a similar, but less significant, recessive effect on preventing stroke in the presence of 2 SHRSP-derived alleles.

Building on the work of Rubattu et al. (1996), Jeffs et al. (1997) designed studies to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischemic insult by performing a genome scan in a F2 cross derived from the SHRSP and the normotensive reference rat strain WKY. They identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 that accounted for 67% of the total variance, colocalized with the genes encoding the atrial and brain natriuretic factors (see 108780 and 600295), and was blood pressure independent.

In a rat model of ischemic stroke, Simard et al. (2006) found upregulation of the cation channel regulatory subunit Sur1 (600509) in ischemic neurons, astrocytes, and capillaries. Upregulation of Sur1 was linked to activation of the transcription factor Sp1 (189906) and was associated with expression of functional nonselective cation channels, which they called the NC(Ca-ATP) channel, but not K(ATP) channels. Treatment with low-dose glibenclamide, which blocks Sur1 and the NC(Ca-ATP) channel, reduced cerebral edema, infarct volume, and mortality by 50%. Simard et al. (2006) concluded that the NC(Ca-ATP) channel is involved in the development of cerebral edema and that targeting Sur1 may provide a new therapeutic approach to stroke.

Arboleda-Velasquez et al. (2008) found that Notch3 knockout increased susceptibility of mice to ischemic challenge. Notch3-null mice showed larger ischemic lesions, more neurologic deficits, increased mortality, more severe cerebral blood flow deficits, and more frequent spontaneous periinfarct depolarizations compared with wildtype mice. Microarray analysis revealed over 600 differentially regulated genes, and all genes that regulate muscle contraction were downregulated.