Genetics in Ischemic Stroke: Current Perspectives and Future Directions
Abstract
:1. Introduction
2. Mechanisms of Ischemic Stroke and Stroke Genetics
2.1. Cerebral Small Vessel Disease
2.2. Large Vessel Disease
2.3. Cardioembolic Stroke
2.4. Embolic Stroke of Undetermined Source
2.5. Mitochondrial Dysfunction
2.6. Haematological Disorders
3. Approaches to the Study of Genetics in Ischemic Stroke
3.1. Linkage Analysis
3.2. Genome-Wide Association Studies (GWASs)
- GWASs predominantly focus on identifying common genetic variants, often those with minor allele frequencies exceeding 1–5% [47]. While rare-variant GWASs are also performed to identify associations between higher-impact rare variants with disease risk, studies are generally underpowered for such analysis due to the large sample size and case control ratios required for discovery [48]. Novel statistical models and methods have been developed for more robust rare-variant GWAS analysis to address this [49].
- GWASs can establish associations between genomic loci and ischemic stroke. With large numbers of loci being identified through GWASs, key challenges remain in interpreting the biological significance of associated loci, in spite of the large repertoire of available tools and methods [50]. For example, a significant locus may be in a non-coding region [51] or exist in linkage disequilibrium with the true causal variant that was captured during sequencing [52], resulting in challenges with biological interpretation.
- Ischemic stroke GWASs have mostly been carried out in populations of European descent. This limits the applicability of various genomic findings, such as PRS and genomic underpinnings of ischemic stroke. This key limitation is further coupled with the heterogenous nature of ischemic stroke, in which population-specific differences could contribute to limited replicability across ethnicities.
4. Genes Related to Ischemic Stroke Occurrence
4.1. Monogenic Ischemic Stroke
4.2. Polygenic Ischemic Stroke
4.3. Polygenic Risk Score
Trial Name | Author and Publication Year | Study Type | Number of Subjects | Ethnicity | Genes Found | Remarks |
---|---|---|---|---|---|---|
STROMICS [57] | Yongjun Wang et al., 2023 | GWAS of all ischemic stroke, LAS, CES, SVS | 10,241 cases, control number was not specified | Chinese | 77 loci (>42% novel) | Largest Chinese GWAS |
GWAS of Intracranial Artery Stenosis (ICAS) [65] | Shogo Dofuku et al., 2023 | GWAS of LAS | 757 (408 cases and 349 controls) | Japanese | rs112735431 in RNF213 | First GWAS of ICAS |
MEGAStroke [55] | Aniket Mishra et al., 2022 | Meta-analysis | >520,000 (67,162 cases and 454,450 controls) | Multi-ancestry (largely European, East Asia and African) | 89 loci (61 novel) (SH3PXD2A, FURIN GRK5 and NOS3) | The largest published GWAS meta-analysis |
COMPASS [58] | Keith L. Keene et al., 2020 | Meta-analysis of any ischemic stroke | >22,000 (3734 cases and 18,317 controls) | African | 1 locus confirmed (rs55931441 near HNF1A gene) 29 other potential variants including those mapped to SFXN4 and TMEM108 genes | Consortium of Minority Population Genome-Wide Association Studies of Stroke |
SiGN Multi-ancestry GWAS [56] | Rainer Malik et al., 2018 | Meta-analysis Of any ischemic stroke, LAS, CES | 521,612 (67,162 cases and 454,450 controls) | Multi-ancestry (Largely European, also East Asian, African, South Asian, mixed Asian and Latin American) | 32 loci(22 novel) CASZ1, WNT2B, KCNK3 for any stroke. CDK6, PDE3A, PRPF8, ILF3-SLC44A2 for any ischemic stroke EDNRA, LINC01492 for LAS RGS7, NKX2-5 for CES | NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium |
GWAS on SVO stroke [66] | Tsong-Hai Lee et al., 2017 | GWAS of SVS | 2073 (342 cases and 1731 controls) | East Asian (Han Chinese) | rs2594966, rs2594973, rs4684776 in ATG7 | |
CHARGE [67] | Audrey Y Chu et al., 2016 | Meta-analysis of any type of stroke | 84,961 (4348 cases and 80,613 controls) | European ancestry | rs12204590 near FOXF2 associated with risk of all-stroke | Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium |
MetaStroke [68] | Traylor M et al., 2012 | GWAS of LAS, CES | 74,393 (12,389 cases and 62,004 controls) | European ancestry | Cardioembolic stroke near PITX2 and ZFHX3 Large-vessel stroke at a 9p21 locus and HDAC9 | Goal to validate associations and identify novel genetic associations for ischemic stroke and its subtypes |
GWAS for large vessel stroke [69] | Hugh S Markus et al., 2012 | GWAS of LAS, CES | 12,140 (5859 cases and 6281 controls) | European ancestry | HDAC9 gene for large vessel stroke PITX2 and ZFHX3 for cardioembolic stroke |
4.4. SARS-CoV-2 Infection and Ischemic Stroke Genetics
5. Genes Related to Stroke Treatment Response: Pharmacogenetics and Pharmacogenomics
5.1. Recombinant Tissue Plasminogen Activator (rtPA):
5.2. Antiplatelet Therapy
5.2.1. Aspirin
5.2.2. Platelet P2Y12 Receptor Antagonist, P2Y12 Inhibitor (Clopidogrel and Ticagrelor)
5.3. Oral Anticoagulants (Warfarin and Direct-Acting Oral Anticoagulants)
6. Genetics of Stroke Recovery
7. Clinical and Translational Applications of Genetics in Ischemic Stroke
- Molecular diagnosis, prognosis, and counselling of patients with typical clinical or radiological phenotypes suggestive of a monogenic disorder, e.g., anterior temporal lobe white matter hyperintensities seen in CADASIL.
- Molecular diagnosis of monogenic disorders in early-onset stroke, stroke with systemic manifestations, or patients with a significant family history.
- Tailoring antiplatelet therapy using pharmacogenetics approaches, e.g., CYP2C19 genotyping for clopidogrel.
- Risk prediction based on common genetic variants using polygenic risk scores.
8. Future Directions
- (1)
- Next-generation sequencing on a large scale
- (2)
- Integration of multi-omics data to understand stroke pathophysiology
- (3)
- Gene therapy
- (4)
- Precision medicine
- (5)
- New drug development
- (6)
- Expanding genetic studies to underrepresented populations
- (7)
- Enhancement of global collaboration
9. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Mechanism of Ischemic Stroke | Disease | Related Genes | Inheritance Pattern | Key Clinical Features |
---|---|---|---|---|
Small vessel disease | CADASIL | NOTCH3 | AD | Migraine, recurrent transient ischemic attacks and lacunar infarcts, vascular cognitive impairment, anterior temporal lobe white matter hyperintensities |
CARASIL | HTRA1 | AR | Similar to CADASIL, but of autosomal recessive inheritance pattern | |
Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) | CTSA | AD | Migraine, transient ischemic attack, recurrent strokes, vertigo, dysphagia, cognitive impairment, REM-sleep behavioral disorder | |
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) | TREX1 | AD | Visual loss, vascular retinopathy, migraine, cognitive impairment microvascular renal disease, Raynaud phenomenon | |
Fabry disease | GAL | X-linked recessive | Transient ischemic attack, stroke. May also be associated with other stroke phenotypes including large vessel disease Acroparasthesias, corneal and lenticular opacities, cardiomyopathy | |
FOXC1-deletion related cerebral small vessel disease | FOXC1 | AD | Hearing impairment, cerebellar malformations, white matter hyperintensities on MRI Brain | |
Type IV collagenopathy | COL4A1 and A2 | AD | Recurrent strokes, seizures, migraine, visual loss, nephropathy, myopathy, arrhythmias, intracranial aneurysms or dolichoectasia | |
Pontine autosomal-dominant microangiopathy with leukoencephalopathy (PADMAL) | COL4A1 | AD | Recurrent lacunar infarcts with predilection to the pons, progressive cognitive impairment | |
Large vessel disease | Ehlers–Danlos Syndrome Type IV | COL3A1 | AD | Facial acrogeria, skin fragility and bruising, large and medium vessel artery dissections, including extracranial and intracranial vertebral and carotid arteries |
Pseudoxanthoma elasticum | ABCC6 | AR | Increased skin elasticity, skin discoloration, ocular angioid streaks | |
Marfan syndrome | FBN1 | AD | Marfanoid features, ascending aorta dissection | |
Moyamoya disease | RNF213 | AD or AR | Steno-occlusive disease of the terminal internal carotid artery with “puff of smoke” collaterals | |
Haematological disorders | Sickle cell disease | HBB | AR | Pain crises, seizures, myelopathy, anemia, thrombosis Can be associated with both large vessel and small vessel infarcts |
Polycythemia rubra vera (PV) | JAK2 | AD or AR | Ischemic stroke due to hyperviscosity state | |
Essential thrombocythemia (ET) | JAK2 MPL | AD or AR | Ischemic stroke due to hyperviscosity state | |
Homocystinuria Hyperhomocysteinemia | CBS italic>MTHFR | AR | Raised plasma homocysteine level, atherosclerosis, thrombosis Classic homocystinuria: ectopia lentis, tall stature, pectus excavatum, developmental delay, thromboembolism | |
Hereditary thrombophilias | Factor V Leiden mutation (FVL) | F5 | AD | Can be associated with small vessel, large vessel, and embolic infarcts |
Prothrombin gene mutation (Factor II mutation) | F2 | AD | ||
Protein C deficiency | PROC | AD or AR | ||
Protein S deficiency | PROS1 | AD or AR | ||
Antithrombin III deficiency | SERPINC1 | AD | ||
Paroxysmal nocturnal hemoglobinuria (PNH) | PIGA | X linked | Complement-mediated hemolysis. Can be associated with small vessel, large vessel and embolic infarcts |
Variant | Gene | Remarks |
---|---|---|
m.3243A>G m.3271T>C m.3252A>G | MT-TL1 | Encodes the transfer RNA for leucine. This mutation results in the disruption of the function of mitochondrial tRNA, affecting protein synthesis within the mitochondria. |
m.13513G>A | MT-ND5 | A part of complex I of the mitochondrial respiratory chain. |
m.8344A>G | MT-TK | Encodes the transfer RNA for lysine. This mutation is more commonly associated with another mitochondrial disorder known as MERRF (Myoclonic Epilepsy with Ragged Red Fibers), but it can sometimes cause MELAS or a MELAS/MERRF overlap syndrome. |
m.14453G>A | MT-ND6 | Associated with MELAS phenotype with dystonia. |
m.13042G>A | MT-ND5 | Associated with MELAS syndrome with a cardiomyopathy phenotype. |
m.8993T>G/C | MT-ATP6 | Associated with NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome, but can sometimes produce MELAS symptoms. |
Drug | Related Genes | |
---|---|---|
Recombinant tissue plasminogen activator (rtPA) or Alteplase | Increased recanalization: PAI-1, TAFI, IL1B, vWF, ACE Increased hemorrhagic conversion: PAI-1, MMP9, FXIII and FXII, A2M, ZBTB46, ACE | |
Aspirin | COX-1, COX-2, P1A1/A2COL1A1, COL1A2, vWF, ITGA2B, UGTIA6*2, ADRA2A, TXBA2R, PLA2G7 | |
Clopidogrel | Hepatic metabolism: CYP3A4, CYP1A2, CYP2C19 Intestinal absorption: ABCB1 Glycoprotein: ABCB1 Platelet surface receptors: P2Y1, P2Y12 | |
Ticagrelor | SLCO1B1, UGT2B7, CYP3A4 | |
Warfarin | VKORC1, and CYP2C9 | |
DOAC | Dabigatran | Activation: CES1, CES2 Transport: ABCB1 Metabolism: UGT1A9, UGT2B7, UGT2B15 |
Rivaroxaban | Transport: ABCB1, ABCG2 Metabolism: CYP3A4/5,CYP2J2 | |
Apixaban | Transport: ABCB1, ABCG2 Metabolism: CYP3A4/5,CYP2J2,CYP1A2 | |
Edoxaban | Transport: ABCB1, SLCO1B1 Metabolism: CES1, CYP3A4/5 | |
Betrixaban | Transport: ABCB1 Metabolism: CYP450-independent hydrolysis |
Trial Name | Author and Publication Year | Study Type | Number of Subjects | Ethnicity | Genes Found |
---|---|---|---|---|---|
Post Stroke Motor Recovery GWAS: A Domain-Specific Approach [110] | Chad M Aldridge et al., 2023 | GWAS | 2100 cases | Not mentioned | No genome-wide significant loci found. 115 SNPs’ subthreshold associations were identified. CLDN23 gene had the most convincing association, which affects blood–brain barrier integrity, neurodevelopment, and immune cell transmigration |
Six GWAS-linked hot loci on stroke outcome [109] | Ruixia Zhu et al., 2021 | GWAS | 982 cases | Northern Chinese | ALDH2 rs10744777, HDAC9 rs2107595, ABO rs532436 (associated with increased stroke recurrence), PATJ rs76221407, LOC105372028 rs1842681, PTCH1 rs2236406 (associated with poor stroke outcome) |
GWAS of functional outcome (GISCOME) [108] | Martin Söderholm et al., 2019 | Meta-analysis | 6165 cases | Europe, US, and Australia | LOC105372028 rs1842681 was associated with brain plasticity and good stroke outcome |
PATJ Variants Are Associated with Worse Ischemic Stroke Functional Outcome [107] | Marina Mola-Caminal et al., 2019 | Meta-analysis | >5000 cases | European ancestry | PATJ (Pals1-associated tight junction) gene (associated with worse functional outcome at 3 months after stroke) |
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Zhang, K.; Loong, S.S.E.; Yuen, L.Z.H.; Venketasubramanian, N.; Chin, H.-L.; Lai, P.S.; Tan, B.Y.Q. Genetics in Ischemic Stroke: Current Perspectives and Future Directions. J. Cardiovasc. Dev. Dis. 2023, 10, 495. https://doi.org/10.3390/jcdd10120495
Zhang K, Loong SSE, Yuen LZH, Venketasubramanian N, Chin H-L, Lai PS, Tan BYQ. Genetics in Ischemic Stroke: Current Perspectives and Future Directions. Journal of Cardiovascular Development and Disease. 2023; 10(12):495. https://doi.org/10.3390/jcdd10120495
Chicago/Turabian StyleZhang, Ka, Shaun S. E. Loong, Linus Z. H. Yuen, Narayanaswamy Venketasubramanian, Hui-Lin Chin, Poh San Lai, and Benjamin Y. Q. Tan. 2023. "Genetics in Ischemic Stroke: Current Perspectives and Future Directions" Journal of Cardiovascular Development and Disease 10, no. 12: 495. https://doi.org/10.3390/jcdd10120495