Ischemic Stroke
Ischemic stroke is a critical medical condition characterized by the interruption of blood flow to a region of the brain due to a blocked blood vessel
Limitations
Section titled “Limitations”Understanding the genetic underpinnings of ischemic stroke is a complex endeavor, and current research, while groundbreaking, operates within certain limitations that affect the interpretation and generalizability of findings. These limitations span methodological challenges, phenotypic variability, and the intricate nature of genetic and environmental interactions.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic studies on ischemic stroke, even those pooling data from thousands of patients, have frequently identified a restricted number of significant genetic loci, suggesting that the individual effects of single-nucleotide polymorphisms (SNPs) on traits like stroke outcomes are often subtle[1]. This implies that the current sample sizes, despite being substantial, might still be insufficient to fully capture the complete spectrum of genetic variation contributing to such a complex condition, potentially leading to an underestimation of its genetic architecture. Consequently, many subtle genetic influences might remain undiscovered, and the identified findings may not yet fully explain the assumed genetic heritability of ischemic stroke[1]. Furthermore, while meta-analyses enhance statistical power by combining data, stringent genome-wide significance thresholds (e.g., p < 5 × 10−8) [2]can overlook variants with smaller, yet biologically important, effects. The need for independent replication to validate novel associations is also crucial, and the absence of immediate replication for some findings can introduce gaps in confidence and potentially inflate effect size estimates for initially reported loci[3].
Phenotypic Heterogeneity and Generalizability Challenges
Section titled “Phenotypic Heterogeneity and Generalizability Challenges”Large-scale collaborative genome-wide association studies (GWAS) inherently combine data from various cohorts, which can introduce a degree of variability in how ischemic stroke and its subtypes are defined or measured across studies[3]. Although researchers strive for standardization in data processing, such as using consistent imputation methods and analytical software, subtle differences in diagnostic criteria, methods for subtyping stroke (e.g., large vessel versus cardioembolic)[4], or the assessment of functional outcomes (e.g., modified Rankin Scale at 3 months) [1]can influence the observed genetic associations. This inherent heterogeneity can dilute genuine genetic signals or introduce noise, making it more challenging to identify robust genetic links. Additionally, the genetic architecture of ischemic stroke can differ among populations. Findings from studies predominantly focused on specific ancestries, such as European-only cohorts[5], may not be fully applicable or generalizable to other diverse groups, including African Americans or multi-ancestry populations [6]. This highlights the ongoing necessity for more inclusive genetic investigations across a broader range of global populations to ensure the universal applicability of findings.
Unaccounted Factors and Unexplained Heritability
Section titled “Unaccounted Factors and Unexplained Heritability”Current genetic research primarily investigates variations in DNA sequences, yet environmental exposures, lifestyle factors, and potential epigenetic modifications are well-established contributors to stroke risk and outcomes[3]. These non-genetic elements can act as significant confounders or interact synergistically with genetic predispositions, thereby altering the expression of genetic variants and influencing disease presentation and recovery. The inability of current studies to fully account for these complex gene-environment interactions limits a comprehensive understanding of ischemic stroke etiology and its progression. Consequently, despite the discovery of numerous genetic loci, a substantial portion of the heritability for ischemic stroke and its functional outcomes remains unexplained[1]. This “missing heritability” suggests that many contributing genetic factors, including rare variants, structural genomic changes, or intricate epistatic interactions, have yet to be identified or thoroughly characterized. Furthermore, the precise biological mechanisms through which many identified genetic variants influence stroke pathology or recovery are often still being elucidated, representing a critical knowledge gap in translating genetic insights into practical clinical applications[4].
Variants
Section titled “Variants”Genetic variations play a significant role in an individual’s susceptibility to ischemic stroke, influencing various biological pathways from blood coagulation to vascular integrity and inflammatory responses. Genome-wide association studies have identified numerous loci that contribute to this complex trait[7]. Understanding these variants provides crucial insights into the underlying mechanisms of stroke.
The ABO gene locus, which determines human blood groups, is strongly associated with the risk of ischemic stroke. Specific variants likers10793962 , rs116552240 , and rs529565 are located within or near this gene and are implicated in this risk. Non-O blood groups (A, B, and AB) are known to be associated with higher plasma levels of von Willebrand factor (VWF) and coagulation Factor VIII, both of which are key components in the blood clotting cascade [8]. Increased levels of these procoagulant factors can lead to a hypercoagulable state, thereby elevating the likelihood of thrombosis and subsequent ischemic stroke. Understanding these genetic influences on blood group phenotypes provides insight into inherited predispositions to stroke.
Variants in genes encoding key coagulation factors significantly influence the risk of ischemic stroke by modulating blood clot formation, a mechanism extensively studied in genome-wide association studies[7]. For instance, variants in the F5 gene, such as rs6025 (Factor V Leiden) and rs1800594 , are particularly notable; rs6025 leads to resistance to activated protein C, increasing the propensity for thrombosis. Similarly, the F11 gene, encoding Coagulation Factor XI, plays a role in the intrinsic pathway of coagulation, and its variantrs4253417 may impact clotting efficiency. The FGB gene, a crucial component of the fibrinogen molecule, is also linked to stroke risk through its variantrs2227402 , as fibrinogen is central to clot structure and blood viscosity [9]. Furthermore, variations like rs1063857 and rs1063856 in the VWF gene, which encodes von Willebrand Factor, can alter platelet adhesion and Factor VIII transport, thereby affecting overall thrombotic potential. These variants collectively highlight the intricate genetic control over hemostasis and its direct relevance to stroke pathology.
Genetic variations affecting the delicate balance of coagulation and anticoagulation pathways, as well as platelet function, contribute to an individual’s susceptibility to ischemic stroke[2]. Variants rs7265317 and rs34234989 in the PROCR gene, which encodes the endothelial protein C receptor, can affect the activation of protein C, a vital anticoagulant. Altered PROCR function may lead to a less effective natural anticoagulant response, thus increasing the risk of thrombotic events. Meanwhile, the KNG1 gene, encoding kininogen, is involved in the kallikrein-kinin system, which regulates blood pressure, inflammation, and coagulation. Its variant rs710446 , along with its associated long non-coding RNA HRG-AS1, may modulate these processes, influencing vascular tone and thrombotic tendencies. Additionally, the STXBP5 gene, with variants like rs9390460 and rs9399599 , is implicated in platelet function and hemostasis, further influencing the risk of clot formation and ischemic stroke[10].
Beyond direct coagulation factors, other genetic loci contribute to ischemic stroke risk by influencing diverse cellular and inflammatory processes[8]. For example, the MCF2L gene, with its variant rs1046205 , is involved in cell signaling and growth, and variations may impact vascular integrity and function. Similarly, the IRF1 gene, encoding Interferon Regulatory Factor 1, plays a crucial role in immune and inflammatory responses. Its variant rs2057655 , along with the associated long non-coding RNA CARINH, could modulate chronic inflammation, a known contributor to atherosclerosis and stroke development. These genes highlight the multifaceted genetic architecture underlying ischemic stroke, extending beyond traditional coagulation pathways to encompass broader vascular and immune mechanisms[7].
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs10793962 rs116552240 rs529565 | ABO | intraocular pressure measurement Red cell distribution width immunoglobulin superfamily containing leucine-rich repeat protein 2 measurement interleukin-1 receptor type 1 measurement level of meprin A subunit alpha in blood |
| rs1046205 | MCF2L | factor VII measurement venous thromboembolism, factor VII measurement circulating fibrinogen levels, factor VII measurement ischemic stroke coronary artery disease, factor VII measurement |
| rs710446 | HRG-AS1, KNG1 | ischemic stroke blood coagulation trait factor XI measurement ESAM/SPINT2 protein level ratio in blood AGRP/NPY protein level ratio in blood |
| rs4253417 | F11 | venous thromboembolism blood protein amount factor XI measurement pulmonary embolism factor XI measurement, circulating fibrinogen levels, tissue plasminogen activator amount, factor VII measurement |
| rs2227402 | FGB | circulating fibrinogen levels, factor VII measurement ischemic stroke venous thromboembolism, circulating fibrinogen levels circulating fibrinogen levels, coronary artery disease |
| rs6025 rs1800594 | F5 | venous thromboembolism ischemic stroke inflammatory bowel disease peripheral arterial disease peripheral vascular disease |
| rs1063857 rs1063856 | VWF | blood coagulation trait von Willebrand factor quality ischemic stroke protein measurement Thromboembolism |
| rs2057655 | CARINH, IRF1 | circulating fibrinogen levels balding measurement sex hormone-binding globulin measurement level of fibrinogen alpha chain in blood low density lipoprotein cholesterol measurement |
| rs7265317 rs34234989 | PROCR | venous thromboembolism, factor VII measurement ischemic stroke circulating fibrinogen levels, factor VII measurement |
| rs9390460 rs9399599 | STXBP5 | von Willebrand factor quality factor VIII measurement myeloid leukocyte count neutrophil count venous thromboembolism |
Definition and Core Concepts
Section titled “Definition and Core Concepts”Ischemic stroke is precisely defined as a neurological deficit that appears acutely and persists for at least 24 hours, or until death if the individual dies within 24 hours of symptom onset[7]. This operational definition establishes a clear temporal criterion for diagnosis. Conceptually, ischemic stroke represents a cerebrovascular event caused by the interruption of blood flow to a part of the brain, leading to cellular damage and neurological impairment. It is critically distinguished from other forms of stroke, such as hemorrhagic strokes and sub-arachnoid hemorrhages, which involve bleeding within or around the brain[7].
Classification Systems and Subtypes
Section titled “Classification Systems and Subtypes”The classification of ischemic stroke relies on standardized nosological systems designed to categorize events based on their underlying etiology. Two prominent systems frequently employed in clinical practice and research are the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification[11]and the Causative Classification of Stroke (CCS) system[12]. These frameworks enable the subdivision of ischemic strokes into distinct subtypes, which is essential for understanding disease mechanisms and tailoring treatments. Common subtypes include large vessel ischemic stroke[4], small vessel stroke (SVS)[3], atherothrombotic, and cardioembolic strokes [7]. Small vessel stroke, for instance, constitutes approximately one-quarter of all ischemic stroke cases, highlighting the clinical significance of these subclassifications[3]. The use of both TOAST and CCS systems is prevalent for subtyping in research studies [13].
Diagnostic Criteria and Measurement Approaches
Section titled “Diagnostic Criteria and Measurement Approaches”The diagnosis of ischemic stroke is primarily based on a combination of clinical criteria and neuroimaging findings[7]. Clinically, the acute onset of neurological symptoms lasting for a specified duration is a key indicator [7]. In research settings, particularly in genome-wide association studies, cases are often meticulously phenotyped and subtyped using established classification systems like TOAST and CCS to ensure diagnostic consistency and enable robust genetic analyses [13]. While not direct diagnostic biomarkers for the acute event, various physiological and biochemical measurements are extensively utilized to characterize individuals with ischemic stroke and identify associated risk factors. These include assessments of blood pressure (systolic and diastolic), fasting plasma glucose, blood hemoglobin A1c content, serum triglycerides, HDL-cholesterol, and LDL-cholesterol, which are often found to differ significantly between subjects with ischemic stroke and control groups[14]. Such measurements provide valuable insights into the metabolic and cardiovascular profiles linked to stroke susceptibility and progression.
Signs and Symptoms
Section titled “Signs and Symptoms”Ischemic stroke manifests as a sudden-onset neurological deficit, with clinical presentations varying significantly based on the affected brain region and the underlying stroke subtype. The identification and characterization of these signs and symptoms are crucial for timely diagnosis, intervention, and prognostic assessment.
Acute Neurological Manifestations and Phenotypic Diversity
Section titled “Acute Neurological Manifestations and Phenotypic Diversity”Ischemic stroke typically presents with acute neurological deficits, reflecting the sudden interruption of blood flow to a specific area of the brain. The clinical picture is highly heterogeneous, encompassing distinct phenotypic presentations such as large vessel ischemic stroke, small vessel stroke, and cardioembolic stroke . For example, a multiancestry GWAS involving over 520,000 subjects identified 32 distinct genetic loci associated with stroke and its various subtypes, underscoring the complex genetic underpinnings of this condition[10]. Furthermore, research suggests a shared genetic susceptibility between ischemic stroke and coronary artery disease, implying common biological pathways that increase the risk for both vascular conditions[15].
The identification of these genetic risk factors often involves large-scale meta-analyses, which combine data from multiple cohorts to detect associations at a genome-wide level. While the identification of common genetic risk factors for stroke has historically presented challenges, ongoing research continues to uncover novel associations[16]. These genetic insights are crucial for understanding the fundamental biological processes that contribute to the development of ischemic stroke, offering potential avenues for risk stratification and therapeutic targets.
Genetic Determinants of Ischemic Stroke Subtypes and Outcomes
Section titled “Genetic Determinants of Ischemic Stroke Subtypes and Outcomes”Genetic research has also elucidated specific variants linked to particular ischemic stroke subtypes, enhancing the precision of risk assessment. For instance, a variant inHDAC9has been strongly associated with large vessel ischemic stroke, with proposed mechanisms suggestingcis-effects on gene expression that may influence arterial health [4]. Similarly, common variants located at 6p21.1 are known to be associated with large artery atherosclerotic stroke, highlighting specific genetic contributions to this common subtype[17]. For cardioembolic ischemic stroke, several intergenic loci, such asrs12646447 and rs72794386 , have been identified as risk factors [2].
Beyond subtype specificities, genetic variants also influence the risk for other manifestations of cerebrovascular disease and patient outcomes. Variants likers11833579 and rs12425791 exhibit stronger associations with atherothrombotic stroke compared to general ischemic stroke, indicating a genotype-phenotype correlation[7]. Genetic risk factors have also been identified for small vessel disease[2], and even for early-onset ischemic stroke, with a specific locus nearHABP2 on chromosome 10q25 being implicated [5]. Additionally, low-frequency variants in the PATJgene have been linked to worse functional outcomes after an ischemic stroke, demonstrating that genetics can influence recovery trajectories[18]. These findings underscore the diverse ways genetic factors contribute to the etiology and prognosis of ischemic stroke across different clinical presentations and populations, including specific risk factors identified in African Americans[6].
Biological Background of Ischemic Stroke
Section titled “Biological Background of Ischemic Stroke”Ischemic stroke, a major global health concern, occurs when blood flow to the brain is interrupted, leading to cellular damage and neurological deficits. Understanding its complex biological underpinnings, from genetic predispositions to molecular pathways and systemic interactions, is crucial for prevention and treatment.
Pathophysiology and Clinical Manifestations of Ischemic Stroke
Section titled “Pathophysiology and Clinical Manifestations of Ischemic Stroke”Ischemic stroke is a primary cause of death worldwide, accounting for 87% of all stroke cases[13]. This severe condition results from a blockage in a blood vessel supplying the brain, which deprives brain tissue of essential oxygen and nutrients [13]. The brain’s high metabolic demand makes it particularly vulnerable to even brief periods of ischemia, leading to rapid cellular dysfunction and death. While ischemic stroke can affect individuals across different age groups, it is notably more common in those over 65 years of age[13].
Ischemic strokes are classified into subtypes based on the size and location of the affected blood vessels and the underlying etiology. Large vessel ischemic stroke (LVS) involves blockages in the major arteries that supply blood to the brain, often due to atherosclerosis[4]. In contrast, small vessel stroke (SVS) results from the occlusion of smaller, penetrating arteries deep within the brain, and it constitutes approximately one-quarter of all ischemic strokes, representing a clinically overt manifestation of small vessel cerebrovascular disease[3]. These distinct pathophysiological mechanisms highlight the varied nature of ischemic stroke and the need for targeted investigations.
Genetic Architecture and Risk Factors for Ischemic Stroke
Section titled “Genetic Architecture and Risk Factors for Ischemic Stroke”Genetic mechanisms play a significant role in determining an individual’s susceptibility to ischemic stroke. Extensive genome-wide association studies (GWAS) have successfully identified numerous genetic variants and loci associated with an increased risk of stroke and its various subtypes[16]. These studies have revealed a complex genetic landscape, identifying specific risk factors across diverse populations, including those of African American ancestry [6]. The collective findings from multiancestry GWAS have led to the discovery of 32 distinct genetic loci associated with stroke and its subtypes, emphasizing the polygenic nature of the condition[10].
Specific genetic regions are often linked to particular stroke subtypes. For instance, a genetic variant in theHDAC9gene has been associated with large vessel ischemic stroke, suggesting that this gene may exert cis-effects on the underlying mechanisms of this subtype[4]. Furthermore, common genetic variants at 6p21.1 have been identified as risk factors for large artery atherosclerotic stroke[17]. For small vessel stroke, genetic variation at 16q24.2 has been implicated[3], and an alternative phenotyping approach has identified an additional genetic risk locus for this subtype [13]. Beyond subtype-specific associations, a locus on chromosome 10q25 near the HABP2gene has been associated with young-onset stroke, indicating unique genetic influences that contribute to stroke risk at younger ages[5].
Molecular Mechanisms and Cellular Impact in Ischemic Stroke
Section titled “Molecular Mechanisms and Cellular Impact in Ischemic Stroke”At the molecular and cellular level, the development and progression of ischemic stroke involve intricate signaling pathways, metabolic disruptions, and alterations in cellular functions. TheHDAC9gene, identified in association with large vessel ischemic stroke, encodes a histone deacetylase[4]. Histone deacetylases are critical enzymes involved in epigenetic regulation, influencing gene expression patterns by modifying chromatin structure, and thus can modulate cellular processes relevant to vascular health and disease development[4].
Other key biomolecules and their associated pathways are also integral to ischemic stroke pathology and outcome. TheHABP2gene, located near a locus associated with young-onset stroke, is relevant due to its potential role in extracellular matrix interactions or coagulation pathways[5]. These processes are fundamental for maintaining vascular integrity and preventing thrombotic events. Additionally, low frequency variants in the PATJgene have been linked to worse functional outcomes following an ischemic stroke[18]. PATJis a protein involved in the formation of tight junctions, which are crucial for maintaining cellular adhesion and barrier functions in tissues, including the brain. Disruptions in these cellular functions can significantly impact brain recovery and rehabilitation potential after a stroke[18]. Platelet reactivity, a vital aspect of the body’s clotting mechanism, also represents a critical molecular pathway, particularly in the context of antiplatelet therapies like clopidogrel, which target platelet function to reduce thrombotic risk [19].
Interconnected Vascular Health and Stroke Subtypes
Section titled “Interconnected Vascular Health and Stroke Subtypes”Ischemic stroke is often intertwined with broader systemic vascular health, reflecting significant tissue and organ-level interactions. There is a recognized shared genetic susceptibility between ischemic stroke and coronary artery disease (CAD), indicating common underlying biological pathways that impact both cerebral and cardiac vasculature[15]. This shared genetic basis suggests that certain genetic variants may contribute to generalized atherosclerotic processes or other vascular dysfunctions that can manifest in different arterial beds throughout the body.
The various subtypes of ischemic stroke, while distinct in their presentation and specific genetic associations, ultimately reflect a spectrum of cerebrovascular pathology. For instance, large artery atherosclerotic stroke is associated with common variants at 6p21.1[17], highlighting the role of atherosclerosis in major brain-supplying arteries. In contrast, small vessel stroke, which accounts for a substantial proportion of all ischemic strokes, has specific genetic associations such as variations at 16q24.2[3]. Furthermore, the presence of cerebral white matter hyperintensities, detectable through neuroimaging, has also been linked to genetic factors in stroke patients, illustrating the intricate relationship between genetic predisposition, disease mechanisms, and their observable impact on brain tissue[3]. Understanding these subtype-specific genetic and pathophysiological distinctions is crucial for developing targeted prevention and effective treatment strategies.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Genetic Regulation of Vascular Remodeling and Thrombosis
Section titled “Genetic Regulation of Vascular Remodeling and Thrombosis”Ischemic stroke pathogenesis involves complex genetic regulation impacting vascular integrity and hemostasis. Genetic variants inHDAC9, encoding histone deacetylase 9, are associated with large vessel ischemic stroke, and these variants can exertcis-effects on disease mechanisms[4]. As a key regulator of gene expression through chromatin modification, dysregulation of HDAC9 can affect vascular smooth muscle cell function and proliferation, contributing to the atherosclerotic processes that narrow large arteries. Similarly, a common coding variant inSERPINA1increases the risk for large artery stroke[10]. SERPINA1 produces alpha-1 antitrypsin, a protease inhibitor, and its altered function can disrupt the protease-antiprotease balance crucial for maintaining extracellular matrix integrity, potentially leading to vascular wall weakening and plaque rupture.
Beyond direct vascular effects, genetic factors also modulate thrombotic processes. Variants at the 6p21.1 locus are associated with large artery atherosclerotic stroke[17], suggesting involvement in mechanisms such as inflammation or lipid metabolism that contribute to plaque formation and stability. Furthermore, genetic variants are linked to overall thrombosis risk [20], altered platelet reactivity [19], and levels of von Willebrand Factor [21]. These genetic influences can lead to an imbalance in hemostasis, promoting pathological clot formation within cerebral vessels, which is a direct cause of ischemic stroke.
Metabolic Pathways and Cellular Homeostasis
Section titled “Metabolic Pathways and Cellular Homeostasis”Metabolic pathways play a crucial role in cellular function and resilience, with their dysregulation contributing to ischemic stroke susceptibility. A novel association ofALDH1L1with ischemic stroke has been identified through analysis of homocysteine and methionine metabolism[21]. ALDH1L1is involved in one-carbon metabolism, a fundamental pathway essential for nucleotide biosynthesis, methylation reactions, and the maintenance of cellular redox balance. Genetic variations affecting the function of ALDH1L1 could lead to metabolic imbalances, potentially increasing oxidative stress, impairing DNA repair mechanisms, or disrupting endothelial function, thereby heightening the risk of ischemic injury. These alterations in metabolic flux can compromise cellular homeostasis, making brain tissue more vulnerable to the energy deprivation characteristic of stroke.
Systems-Level Integration and Shared Susceptibility
Section titled “Systems-Level Integration and Shared Susceptibility”Ischemic stroke arises from a complex interplay of genetic and environmental factors, with significant systems-level integration evident across various disease mechanisms. There is shared genetic susceptibility between ischemic stroke and coronary artery disease, highlighting common underlying pathways in cardiovascular pathology[15]. This overlap suggests that a network of genes influencing processes such as inflammation, lipid transport, and vascular remodeling contributes to the risk of both conditions, indicating pathway crosstalk. Genome-wide association studies have identified numerous risk loci for stroke and its various subtypes[2], [22], [10], underscoring the polygenic nature of the disease. These findings point to network interactions where multiple genetic variants, each with a small effect, cumulatively influence disease risk through hierarchical regulation of interconnected biological systems, leading to emergent properties in stroke susceptibility and manifestation.
Cellular Integrity and Functional Outcome Pathways
Section titled “Cellular Integrity and Functional Outcome Pathways”The integrity of cellular structures and their capacity for repair significantly influence the functional outcome following an ischemic stroke. Low frequency variants inPATJ(PALS1-associated tight junction protein) are associated with worse ischemic stroke functional outcome[18]. PATJ is a critical component in maintaining cell polarity and the structural integrity of tight junctions, particularly in endothelial cells of the blood-brain barrier and in various neural cell types. Dysregulation of PATJ, influenced by specific genetic variants, could compromise the barrier function, leading to increased vascular permeability and exacerbating brain injury during ischemia. Furthermore, its role in cell-cell adhesion and signaling pathways may affect neuronal and glial cell resilience and post-stroke reparative processes, thereby impacting the brain’s ability to recover and influencing long-term functional recovery.
Clinical Relevance
Section titled “Clinical Relevance”Ischemic stroke, a leading cause of disability and mortality worldwide, has complex genetic and environmental underpinnings. Advanced genomic research, particularly genome-wide association studies (GWAS), has significantly enhanced the understanding of its pathophysiology, risk factors, and prognostic indicators. These insights are crucial for refining clinical approaches, from early risk assessment to personalized treatment and long-term care strategies.
Genetic Risk Stratification and Personalized Prevention
Section titled “Genetic Risk Stratification and Personalized Prevention”Genetic studies have profoundly impacted the ability to identify individuals at elevated risk for ischemic stroke, moving towards more personalized prevention strategies. Multiple genetic loci have been identified across diverse populations, including specific risk factors for stroke in African Americans[6]. For instance, variants in HDAC9have been linked to large vessel ischemic stroke[4], while variations at 6p21.1 are associated with large artery atherosclerotic stroke[17]. Furthermore, specific genetic variations at 16q24.2 have been associated with small vessel stroke[3], a subtype that accounts for approximately one-quarter of all ischemic strokes. These findings are pivotal for refining risk stratification, enabling the identification of high-risk individuals and informing tailored primary prevention efforts [2]. By delineating the genetic predispositions for specific stroke subtypes, clinicians can develop more targeted interventions, optimizing patient care beyond traditional risk factor management.
The identification of numerous genetic loci associated with various stroke subtypes, including 32 loci from a multiancestry GWAS involving over 520,000 subjects[10], allows for a more granular approach to patient care. This genetic information can enhance diagnostic utility by helping to classify stroke subtypes and guide the selection of appropriate preventive measures[22]. While the effect sizes of individual single nucleotide polymorphisms (SNPs) on stroke risk might be small, their cumulative impact, especially within specific populations, contributes to a comprehensive risk profile. This understanding supports precision medicine approaches, potentially leading to more effective, individualized prevention strategies by integrating genetic insights into clinical practice[1].
Prognostic Assessment and Therapeutic Guidance
Section titled “Prognostic Assessment and Therapeutic Guidance”Genetic factors significantly influence the prognosis and functional outcome following an ischemic stroke, offering valuable insights for therapeutic guidance and rehabilitation planning. Specific low-frequency variants in thePATJgene, for example, have been associated with worse functional outcomes in ischemic stroke patients[18]. This prognostic information, often assessed using measures like the modified Rankin Scale (mRS) at 3 months post-stroke[1], can aid clinicians in predicting disease progression and long-term implications for patient care, including the intensity and duration of rehabilitation strategies[18]. Although genome-wide meta-analyses involving thousands of patients have identified significant loci impacting outcome, the overall genetic variation for ischemic stroke outcomes is complex, indicating that the effects of individual SNPs are typically modest[1].
Beyond predicting functional recovery, genetic insights can inform monitoring strategies and personalize treatment responses. Genome-wide meta-analyses have explored genetic associations with cerebral white matter hyperintensities in stroke patients[3], which are often indicative of underlying small vessel disease and can influence long-term cognitive and functional trajectories. Understanding these genetic predispositions can help identify patients who may benefit from more aggressive monitoring for specific complications or who might respond differently to particular therapeutic interventions. This precision can optimize post-stroke management, facilitate personalized rehabilitation planning, and ultimately improve patient outcomes.
Overlapping Phenotypes and Comorbidity Management
Section titled “Overlapping Phenotypes and Comorbidity Management”Ischemic stroke frequently shares genetic predispositions and clinical associations with other cardiovascular and cerebrovascular conditions, underscoring the necessity of an integrated approach to patient management. Research has revealed a shared genetic susceptibility between ischemic stroke and coronary artery disease through genome-wide analyses of common variants[15]. This overlap suggests that individuals at risk for one condition may also be at an elevated risk for the other, necessitating comprehensive cardiovascular risk assessment and management strategies. Furthermore, specific genetic loci identified for stroke are also linked to small vessel disease[2], a condition that manifests with clinically overt small vessel stroke and other complications such as cerebral white matter hyperintensities[3].
The intricate relationship between ischemic stroke and associated conditions extends to inflammatory pathways. Genome-wide association studies have investigated the genetic determinants of white blood cell counts in patients with ischemic stroke[23], indicating potential shared biological mechanisms that contribute to both stroke pathogenesis and systemic inflammatory responses. Recognizing these overlapping phenotypes and shared genetic underpinnings is crucial for identifying related conditions, anticipating complications, and developing integrated prevention and treatment strategies. This holistic view ensures that patient care addresses the full spectrum of cardiovascular and cerebrovascular health, moving towards more effective, broad-based prevention and management.
Frequently Asked Questions About Ischemic Stroke
Section titled “Frequently Asked Questions About Ischemic Stroke”These questions address the most important and specific aspects of ischemic stroke based on current genetic research.
1. My family has a stroke history; can my healthy habits really protect me?
Section titled “1. My family has a stroke history; can my healthy habits really protect me?”Yes, maintaining healthy habits significantly reduces your risk, even with a family history. While genetics contribute to stroke risk, managing traditional factors like hypertension, diabetes, and avoiding smoking are well-established ways to lower your chances. It’s about balancing your inherited predisposition with actionable lifestyle choices.
2. Is a DNA test actually useful for finding my stroke risk?
Section titled “2. Is a DNA test actually useful for finding my stroke risk?”While genetic studies have identified many variants linked to stroke, like a variant inHDAC9for large vessel stroke, these currently explain only a small fraction of the total inherited risk. The effects of individual genetic variants on stroke risk are often subtle. Therefore, a single DNA test might not give you a complete picture of your overall risk.
3. I’m not European; does my ancestry affect my stroke risk?
Section titled “3. I’m not European; does my ancestry affect my stroke risk?”Yes, the genetic architecture of ischemic stroke can differ among various populations. Many genetic findings have come from studies predominantly focused on specific ancestries, such as European cohorts. This means that findings might not be fully applicable or generalizable to other diverse groups, highlighting the need for more inclusive research.
4. My doctors can’t explain my stroke risk; could my genes be why?
Section titled “4. My doctors can’t explain my stroke risk; could my genes be why?”Yes, a significant portion of stroke risk remains unexplained by traditional factors, strongly suggesting an important role for genetic predisposition. Despite identifying numerous genetic loci, a substantial part of the heritability for ischemic stroke is still “missing,” implying many contributing genetic factors are yet to be discovered.
5. Why do some seemingly healthy people still get strokes?
Section titled “5. Why do some seemingly healthy people still get strokes?”Even in individuals without traditional risk factors like high blood pressure or diabetes, genetic predisposition plays a role. Genome-wide association studies have identified dozens of genetic variants linked to stroke and its subtypes. These genetic factors can contribute to risk even when lifestyle choices appear to be healthy.
6. Do my genes affect how well I recover from a stroke?
Section titled “6. Do my genes affect how well I recover from a stroke?”Yes, genetic factors can influence functional outcomes after an ischemic stroke. While the individual effects of specific genetic variants on recovery are often small, they contribute to how your body responds to the damage and its capacity for healing and rehabilitation.
7. Can my good lifestyle really overcome my family’s stroke genes?
Section titled “7. Can my good lifestyle really overcome my family’s stroke genes?”While you can’t change your genes, a good lifestyle is a powerful tool. Managing traditional risk factors such as hypertension, atrial fibrillation, diabetes, and avoiding cigarette smoking can significantly reduce your overall stroke risk, even if you have a genetic predisposition. It’s about proactive risk reduction.
8. I’m not old; do my genes matter for stroke risk yet?
Section titled “8. I’m not old; do my genes matter for stroke risk yet?”Yes, genetic predispositions for ischemic stroke are present throughout your life, not just in older age. While ischemic stroke often affects individuals over 65, these genetic factors can interact with environmental exposures and lifestyle choices over time, influencing your risk profile long before you reach older adulthood.
9. My relative had a specific stroke type; does that change my genetic risk?
Section titled “9. My relative had a specific stroke type; does that change my genetic risk?”Yes, genetic variants can be associated with specific stroke subtypes. For instance, a variant in theHDAC9gene is linked to large vessel ischemic stroke, and other genetic loci have been identified for small vessel disease. Understanding the specific subtype can offer more refined insights into potential genetic predispositions within your family.
10. Does stress or my daily habits really matter if I have stroke genes?
Section titled “10. Does stress or my daily habits really matter if I have stroke genes?”Yes, absolutely. Environmental exposures, lifestyle factors (like diet and exercise), and even epigenetic modifications are well-established contributors to stroke risk and can interact with your genetic predispositions. These non-genetic elements can significantly influence how your genetic variants are expressed, affecting your overall disease risk and progression.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Soderholm M et al. “Genome-wide association meta-analysis of functional outcome after ischemic stroke.”Neurology, 2019. PMID: 30796134.
[2] Chauhan G, et al. “Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.”The Lancet Neurology, 2016.
[3] Traylor M et al. “Genetic variation at 16q24.2 is associated with small vessel stroke.”Ann Neurol, 2017. PMID: 27997041.
[4] Bellenguez C et al. “Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.”Nat Genet, 2012. PMID: 22306652.
[5] Cheng YC et al. “Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.”Stroke, 2017. PMID: 26732560.
[6] Carty, C. L., et al. “Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.”Stroke, 2015.
[7] Ikram MA, et al. “Genomewide Association Studies of Stroke.”The New England Journal of Medicine, vol. 360, no. 17, 2009, pp. 1718-1728.
[8] Pulit SL, et al. “Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.”The Lancet Neurology, vol. 15, no. 1, 2015, pp. 4-7.
[9] Williams, SR. et al. “Genetic Drivers of von Willebrand Factor Levels in an Ischemic Stroke Population and Association With Risk for Recurrent Stroke.”Stroke, vol. 49, no. 6, 2018, pp. 1324-1331.
[10] Malik R, et al. “Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.”Nature Genetics, vol. 50, no. 4, 2018, pp. 524-537.
[11] Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.Stroke. 1993;24:35-41.
[12] Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: The causative classification of stroke system.Stroke. 2007;38:2979-84.
[13] von Berg J, Giese AK, Furey TS, et al. Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke.Eur J Hum Genet. 2020 Jun;28(6):798-808.
[14] Yamada Y, Kato K, Oguri M, et al. Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.Biomed Rep. 2018 Jul;9(1):47-53.
[15] Dichgans, M. et al. “Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.”Stroke, vol. 45, no. 1, Jan. 2014, pp. 24-30.
[16] Matarin, M. et al. “A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release.”Lancet Neurology, vol. 6, no. 4, Apr. 2007, pp. 325-30.
[17] Holliday EG et al. “Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.”Nat Genet, 2012. PMID: 22941190.
[18] Mola-Caminal M et al. “PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.”Circ Res, 2018. PMID: 30582445.
[19] Verma, SS. et al. “Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC).”Clin Pharmacol Ther, vol. 108, no. 4, 2020, pp. 836-848.
[20] Hinds, DA. et al. “Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.” Hum Mol Genet, vol. 25, no. 8, 2016, pp. 1673-1681.
[21] Williams SR, et al. “Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke.”Neurology, vol. 87, no. 3, 2016, pp. 272-280.
[22] Pulit SL et al. “Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.”Lancet Neurol, 2016. PMID: 26708676.
[23] Torres-Aguila, N. P., et al. “Genome-Wide Association Study of White Blood Cell Counts in Patients With Ischemic Stroke.”Stroke, vol. 50, no. 12, 2019, pp. 3362-3370.