Abstract
Ischemic stroke, which is caused by blockage of vessels supplying blood to the brain, represents approximately 87% of all strokes in the United States. While a significant heritable component to ischemic stroke has been established, it is also clear that stroke is not a single “disease” but rather represents a heterogeneous collection of conditions with different pathogeneses. Genetic causes have been identified for a handful of monogenic syndromes that include stroke, but even collectively these conditions are very rare. To date, at least 10 robustly replicated susceptibility loci for nonmonogenic ischemic stroke have been identified, most of which are associated with specific stroke subtypes (especially large artery or cardioembolic stroke). The challenge will be to make sense of the known and to be discovered stroke susceptibility genes and to translate this knowledge into clinical benefit.
Keywords
Ischemic stroke, genetics, heritability, monogenic, Mendelian, genomewide association study, review, pharmacogenetics, familial aggregation
Chapter Outline
Introduction 277
Phenotypic Heterogeneity of Stroke 278
Familial Aggregation of Ischemic Stroke 279
Monogenic Syndromes that Include Stroke 281
Genes Associated with Common Forms of Ischemic Stroke 281
Using Genomewide SNPs to Estimate Stroke Heritability and Genetic Overlap Shared Between Stroke and Other Disorders 285
Clinical Applications of Genetics in Stroke 285
Conclusion 287
References
Introduction
Stroke is a devastating disease that results from the sudden occlusion or rupture of a blood vessel supplying the brain, with interrupted blood flow to the brain leading to cell death. It is estimated that 6.6 million Americans over the age of 20 have experienced a stroke, corresponding to an overall stroke prevalence of 2.6% , and that one in five women and one in six men will experience a stroke sometime during their lifetime . Prevalence is even higher among African-Americans and American Indians. The prevalence of silent cerebral infarction varies widely with most estimates in the 10%–20% range, depending on age . When considered separately from cardiovascular diseases, stroke ranks as the second leading cause of death worldwide and fourth leading cause of death in the United States . Among stroke survivors, the majority are left with permanent neurologic impairments, making stroke a major cause of long-term disability.
Prevention efforts are currently limited to management of stroke risk factors. The primary risk factors for stroke include high blood pressure, diabetes mellitus, disorders of heart rhythm (e.g., atrial fibrillation), dyslipidemia, smoking, physical inactivity, obesity, nutrition, chronic kidney disease, sickle cell disease, and, among women, postmenopausal hormone use and oral contraceptive use. Family history of stroke is also a well-documented risk factor for stroke. A major impediment to stroke prevention has been the lack of understanding at the molecular level of the physiologic changes that leads to stroke susceptibility, as well as the proximal events that initiate stroke. In the multinational WHO MONICA Study, measured risk factors, primarily smoking and elevated blood pressure, explained 21% of the variation in stroke incidence among the population in men and 42% in women . The contribution of these factors may come down as smoking rates in the population continue to decrease and with continued improvements in hypertension control at the population level.
One approach toward improving understanding of the molecular underpinnings of stroke is to identify stroke susceptibility genes and then to study what these genes do. Identification of novel stroke susceptibility genes might uncover new pathways that could be targeted for stroke prevention. In this chapter, we first describe the heterogeneity of stroke and then summarize the evidence for a genetic contribution to stroke and review the status of current efforts to map genes for ischemic stroke. The focus of this chapter is on the common forms of ischemic stroke, as opposed to some of the rare Mendelian disorders, in which stroke may occur as part of the clinical presentation.
Phenotypic Heterogeneity of Stroke
Efforts to uncover the genetic contributors to stroke susceptibility must consider that stroke is not a single “disease” but rather represents a heterogeneous collection of conditions with different pathogeneses, all resulting in the interruption of blood flow to the brain. Strokes can be of the ischemic (the focus of this chapter) or hemorrhagic types. Ischemic strokes, caused by blockage of vessels supplying blood to the brain, represent approximately 87% of all strokes in the United States. In contrast, hemorrhagic strokes, which are caused by rupture of the vessels with subsequent bleeding into the surrounding brain, account for the remaining 13% of all strokes .
Within ischemic stroke, events can be further subclassified on the basis of clinical features and other diagnostic criteria. The most commonly used stroke subtyping classification system is the Trial of Org 10172 in Acute Stroke Treatment classification system that was originally developed to predict therapeutic response to anticoagulation for acute ischemic stroke. The Causative Classification of Stroke (CCS) system, which was developed more recently, incorporates additional clinical symptoms and makes greater use of results from neuroimaging and other ancillary examinations to obtain a comprehensive evaluation of subtype . Both systems classify ischemic strokes into categories corresponding to their presumed etiology. These include large artery stroke (originating from thrombosis or embolism due to atherosclerosis of a large artery), cardioembolic stroke (emboli originating in the heart), small artery/lacunar stroke (occlusion of small vessels in the brain), stroke due to other determined etiology (e.g., stimulant drug use, hypercoagulable states, hematological disorders, nonatherosclerotic vasculopathies), or strokes due to undetermined etiology. Fig. 15.1 shows the distribution of subtypes among first-ever ischemic stroke patients participating in the population-based Greater Cincinnati/Northern Kentucky Stroke Study .
Familial Aggregation of Ischemic Stroke
A large number of studies have demonstrated that ischemic stroke aggregates in families more often than expected by chance. In a review of nearly 40 studies, Flossman et al reported that having a positive family history of stroke was associated with an approximately 30% to 76% increase in stroke risk, with differences in these estimates attributable to a variety of factors related to study design, ascertainment of cases, ages of study subjects, etc. In a systematic analysis performed in the Framingham Heart Study, a parental history of ischemic stroke by 65 years of age was found to be associated with a threefold increase in ischemic stroke risk in offspring, and this declined only slightly after adjusting for conventional stroke risk factors . Based on twin studies, Bak et al. reported a heritability of 32% for stroke death and 17% for stroke hospitalization or stroke death in twins, reflecting that genetic factors account for up to one-third of stroke deaths and slightly less than one-fifth of hospitalizations . At least part of the familial aggregation in ischemic stroke may be due to familial clustering of ischemic stroke risk factors.
The heritable component of stroke subtypes is less well-defined, although available studies suggest less familial aggregation for cardioembolic stroke than for other subtypes. In a large clinic-based study from the United Kingdom, a family history of vascular disease was reported to be significantly associated with both large artery and small artery stroke, but not with cardioembolic stroke nor strokes of undetermined etiology . In the Sahlgrenska Academy Study on Ischemic Stroke, a family history of stroke was significantly associated with overall ischemic stroke, large vessel stroke, small vessel stroke, and cryptogenic stroke, but like the UK study, not associated with cardioembolic stroke . In two population-based studies also from the United Kingdom, a family history of stroke was again found to be less frequent in cases with cardioembolic stroke compared to cases with other subtypes . There is very little data as to whether affected family members tend to have the same subtype within multiplex families.
At least two case–control studies have been performed in patients with stroke aged <50 years, each reporting stroke to be associated with a positive family history of stroke, with ORs ranging from 1.2 to 3.2 . Available evidence suggests that a family history of stroke may be a stronger risk factor for young-onset stroke than for older onset ischemic stroke, as has been reported. Flossman, for example, reported slightly stronger association of stroke with family history of stroke in cases with onset aged <70 years than in those with onset age 70 years , although this study compared estimates obtained across multiple studies. Cheng et al. reviewed 11 studies employing case–control, case-only, or cohort designs that specifically compared the association of family of stroke with stroke between early- and later onset stroke cases and concluded that nearly all supported a stronger association for an earlier onset of stroke . Notably, this was true for both of the cohort studies, one from Finland reporting that the relative risk of incident stroke associated with family history was stronger in men aged 25 to 49 years than in men aged 50 to 64 years (relative risk (RR)=2.82 versus 1.65) with similar associations observed for women and the other from Framingham reporting a stronger effect of parental history of IS was observed for risk of IS in the offspring at younger age (<65 years) compared with stroke risk in offspring at any age (RR=3.16 versus 2.22) .
While the relatively stronger degree of familial aggregation observed in younger onset stroke could reflect a stronger genetic load in younger cases, it is also possible that differing degrees of familial aggregation between younger and older cases could relate to the differing distributions of stroke subtypes between the young and the old. Direct comparisons of subtype distributions between older and younger cases are complicated by the fact that case ascertainment is often through hospitals and may not be representative of the full spectrum of strokes occurring in the population. Nevertheless, available data suggest that younger cases tend to have proportionately less large artery stroke and more strokes due to other determined causes compared to older onset cases .
Monogenic Syndromes that Include Stroke
Although the specific genes associated with ischemic stroke are largely unknown, there are a small number of syndromes and conditions that segregate as Mendelian traits and in which ischemic stroke may appear as one of the clinical manifestations. One feature that these stroke-associated single-gene disorders have in common is that they generally begin at an early age and affect multiple organ systems. Although these disorders are individually rare, they are important for several reasons, foremost being that specific treatments are available for some of these disorders (e.g., enzyme replacement therapy for Fabry’s and transfusion therapy for sickle cell disease). Identifying these disorders also provides opportunities to identify undiagnosed cases in family members (e.g., cascade screening) and to provide genetic counseling to patients and to families of affected individuals.
Representative monogenic stroke-associated syndromes are summarized in Table 15.1 . The seven forms described are caused by mutations affecting different biological processes. Small vessel phenotypes can be caused by multiple mechanisms (e.g., through defective NOTCH3 receptor protein in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, defective TGF-β signaling in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, autoimmune reactivity in retinal vasculopathy with cerebral leukodystrophy). Similarly, phenotypes with either large or small vessel disease can have diverse causes (e.g., endotheliopathy due to buildup of glycolipids in Fabry’s disease and misshapen hemoglobin in sickle cell disease). Ischemic stroke can even be due to mechanisms that have nothing to do with the blood vessels, such as impaired energy metabolism in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. Those defects across these multiple biologic systems can all lead to stroke illustrates the multifactorial and polygenic nature of stroke.
| Disorder | Gene | Inheritance | Relation of Genetic Defect to Stroke |
|---|---|---|---|
| CADASIL | NOTCH3 | Autosomal dominant | Abnormal Notch3 receptor protein leads to impairment of vascular smooth muscle cells |
| CARASIL | HTRA1 | Autosomal recessive | Defective signaling of TGF-β, leading to altered structure of small blood vessels |
| Fabry’s disease | GLA | X-linked | The defective enzyme encoded by this gene prevents breakdown of a glycolipid, whose subsequent buildup damages variety of organ systems, including blood vessels |
| RCVL a | TREX1 | Autosomal dominant | Encodes a protein that may play a role in DNA repair. Disease is perhaps immune-mediated, with small vessel damage occurring as result of accumulated DNA and RNA products |
| Sickle cell disease | HBB | Autosomal recessive | Defect in beta-globulin subunit of hemoglobin, causing misshapen red blood cells that may lodge in small blood cells |
| MELAS | mtDNA | Maternal | Can result from mutations in several different mitochondrial genes, especially MT-TL1 , that impair ability of mitochondria to produce proteins, use oxygen, and produce energy. Stroke thought to be related to ensuing impairments in energy metabolism and buildup of lactic acid |
| Moyamoya disease | RNF213 and others | Autosomal; dominant with incomplete penetrance? | Genetic defect unknown but leads to constriction of internal carotid artery and downstream vessels |
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