Stroke Genetics

This revised, expanded third edition updates the reader on this fast moving field as well providing an overall understanding of the genetics of complex diseases by using stroke as a paradigm. The reader will gain a comprehensive understanding of cerebrovascular genetics including the epidemiological evidence for the genetic basis of ischemic and hemorrhagic stroke, knowledge of its molecular basis from association, linkage and recent genome-wide studies, and also monogenic disorders. Finally, the legal and ethical complexities in dealing with these issues are discussed. Stroke Genetics is a valuable resource for neurologists, stroke physicians, hypertension specialists, internists, clinical pharmacologists and those in training, as well as researchers in the field of disease genetics. Each chapter now contains teaching/training MCQs to help with retention of information learnt from each chapter and this will be of considerable use to those training or about to the examined inthe field of inherited stroke. Additional questions via app: Download the Springer Nature Flashcards app for free and use exclusive additional material to test your knowledge. Preface Reference Acknowledgments Contents Chapter 1: Introduction Evidence for Heritability of Stroke from Twin and Family History Studies Available Genetic Strategies The Practicing Neurologist and Stroke Physician Undertaking a Genetic Stroke Clinic Specific Procedures Conclusion Chapter 2: Familial Occurrence and Heritability of Stroke Introduction Establishing the Heritability of Stroke Twin Studies to Investigate the Genetic Epidemiology of Stroke Parental Stroke and Risk of Stroke in Offspring Risk of Stroke Between Siblings Age at Onset with Familial Aggregation of Stroke Family History and Sex Differences in Stroke Risk Family History and Differences in Risk of Stroke Observed by Race and Ethnicity Familial Aggregation by Ischemic Stroke Phenotype Challenges in Family History Studies of Stroke Research Application in Genetic Studies Clinical Application Future Considerations References Chapter 3: Genetic Association Studies and Next Generation Sequencing in Stroke: Methods Introduction Study Designs Family Based Studies Genome Wide Association Meta-Analysis in Genetic Association Studies Imputation in GWAS Meta-Analysis Meta-Analysis Following Imputation: Genome Wide Association Meta-Analysis (GWAMAs) Sources of Bias in Genetic Association Studies Misclassification of Cases and Controls Misspecification of Outcomes Multiple Comparisons Population Stratification Genotyping Related Errors Genotyping Measurement Error Quality Control Measures Hardy-Weinberg Equilibrium Filtering Based on Call Rates, Missingness and Pairwise Relatedness Analysis for Association Meta-Analysis Mendelian Randomization-Another Option for Investigating Genetic Association Next Generation Sequencing (NGS) Polygenic Risk Scores Conclusion References Chapter 4: Sickle Cell Disease Introduction Prevalence and Incidence Stroke Risk Stratification of SCD Patients Pathophysiology Anemia and Hypoxemia Reduced Nitric Oxide Availability Platelet Aggregation Endothelial Activation RBC Dehydration Role of Inflammation in Stroke Associated with SCD Inflammatory Vasculopathy Inflammatory Mediators Vascular Cellular Adhesion Molecule (VCAM) Tumor Necrosis Factor Interleukin 4 Receptor Leukotriene C4 Synthase (LTC4S) Interleukin-1 Beta (IL-1 Beta) Non-genetic Inflammatory Biomakers Management of SCD and SCD-Related Stroke Clinical Symptoms and Signs of Stroke in SCD Work Up of Acute Stroke in SCD Neuroimaging Laboratory Investigations Treatment of Stroke in SCD Treatment of Acute Stroke in Children with SCD Treatment of Acute Stroke in Adults with SCD Primary Stroke Prevention in SCD Secondary Stroke Prevention in SCD The Role of Hydroxyurea Complications Associated with Management of Stroke in SCD and Alternative Strategies New Therapeutic Approaches for Treatment of Sickle Cell Disease Inducers of Fetal Hemoglobin (HbF) Inhibition of K+-Cl Co-transport Inhibition of the Gardos Channel Nitric Oxide/Arginine Anti-inflammatory Agents Statins Corticosteroids New Therapies Future Directions Impact of Coronavirus Disease 2019 (COVID-19) COVID-19 Infection Conclusions References Chapter 5: Fabry Disease Introduction Clinical Presentation Neurological Manifestations: PNS and CNS Involvement Stroke and Cerebrovascular Disease Epidemiology Clinical Features Neuroimaging Pathogenesis Diagnosis, Treatment, and Monitoring Conclusion References Chapter 6: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Introduction Diagnosis and Prevalence Main Clinical Features Imaging and Biological Features Pathological Data Genetics Treatment References Chapter 7: Stroke-Like Episodes in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Introduction Overview of the Mitochondria and Mitochondrial Disease Genetics and Molecular Pathophysiology of MELAS Clinical and Diagnostic Features of MELAS Stroke-Like Episodes Radiographic Features of Stroke-Like Episodes Pathogenesis of Stroke-Like Episodes Neuronopathy Hypothesis Angiopathy Hypothesis Diagnostic Evaluation Laboratory Analysis Muscle Biopsy Molecular Diagnostics Treatment Supplementation and Diet Disease Modifying and Symptomatic Therapy Drugs Preimplantation Genetics and Gene Therapy When to Think of MELAS Syndrome Conclusion References Chapter 8: Other Monogenetic Stroke Disorders Introduction Definition of Terms Monogenetic or Mendelian Disorders Diagnostic Approach to Suspected Monogenetic Stroke Disorder Monogenetic Cerebral Small Vessel Disease Responsible Genetic Testing Conclusion References Recommended Review Articles Chapter 9: The Genetics of Cerebral Microbleeds Introduction What Are Cerebral Microbleeds? The Clinical Relevance of Cerebral Microbleeds in Non-genetic (Sporadic) Disorders Identifying Cerebral Small Vessel Disease Subtype Risk of Stroke Events Other Clinical Associations Cerebral Microbleeds in Familial Cerebral Amyloid Angiopathies Amyloid-Beta Cerebral Amyloid Angiopathy Cerebral Microbleeds in Familial CAA Due to Mutations of APP Point Mutations Copy Number Variants Cerebral Microbleeds and Presenilin Mutations Other (Non-amyloid-beta) Cerebrovascular Amyloid Angiopathies Familial British Dementia Gelsolin Amyloidosis Familial Leptomeningeal (Transthyretin) Amyloidosis Cerebral Microbleeds in Other, Non-amyloid Related, Inherited Cerebral Small Vessel Diseases CADASIL CARASIL Autosomal Dominant HTRA1 Related Cerebral Small Vessel Disease CARASAL COL4A1 and COL4A2 Fabry Disease TREX1 LAMB1 Genome Wide Association Studies (GWAS) Summary References Chapter 10: The Genetics of Cerebral Aneurysms and Other Vascular Malformations Introduction Intracranial Aneurysms Epidemiology and Prevalence Genetics of Familial and Sporadic Intracranial Aneurysms Familial (Non-hereditary) Intracranial Aneurysms Screening Intracranial Aneurysms in Hereditary Disorders Autosomal Dominant Polycystic Kidney Disease Epidemiology Genetics Screening Neurocutaneous Syndromes Connective Tissue Diseases Other Diseases Arteriovenous Malformations Epidemiology and Natural History Etiology and Pathogenesis Sporadic AVM Genetics Genetic Syndromes Associated with Brain AVMs Hereditary Hemorrhagic Telangiectasia Capillary Malformation-Arteriovenous Malformation Syndrome Parkes Weber Syndrome PTEN Mutations Other AVM Syndromes Cavernous Malformations Histopathological Characteristics Epidemiology and Natural History Hereditary Versus Sporadic Cavernous Malformations Pathogenesis of Cavernous Malformations Familial Cavernous Malformation Syndromes Indications for Genetic Testing and Imaging Screening References Chapter 11: Intracerebral Hemorrhage and Cerebral Amyloid Angiopathy Introduction Intracerebral Hemorrhage: A Cerebral Small Vessel Disease Genetic Variation and Risk of ICH Cerebral Amyloid Angiopathy and Intracerebral Hemorrhage Sporadic CAA-Related ICH Common Genetic Variation and Sporadic CAA-ICH Apolipoprotein E (APOE) Other Sporadic CAA-ICH Risk Loci Familial CAA COL4A1/COL4A2 Related Intracerebral Hemorrhage Deep Hemispheric (Hypertensive) ICH Conclusion/Future Directions References Chapter 12: White Matter Disease Introduction Epidemiology, Neuroimaging, and Clinicopathological Correlates of White Matter Disease Genetic Architecture of Cerebrovascular White Matter Disease WMH Heritability and Results of the Linkage and Candidate Gene Studies Single-Gene Disorders Associated with White Matter Disease Complex Disease Genetics and Cerebral White Matter Disease Conclusion References Chapter 13: Genetics of Small Vessel Disease Introduction Definitions and Epidemiology Genetic Basis of CSVD Sporadic Genetic Associations with CSVD White Matter Hyperintensities Small Vessel Stroke Intracerebral Hemorrhage Non-lobar ICH Lobar ICH (CAA-Related) Combining Genetics of CSVDs and Related Neurological Disorders Cerebral Microbleeds and Perivascular Spaces Vascular Dementia Monogenic Syndromes with CSVD CADASIL (NOTCH3) CARASIL (HTRA1) Fabry Disease (α-GAL) COL4A1 and COL4A2 Other Mendelian Disorders (TREX1, FOXC) Amyloid-Related Mendelian Disorders (APP) Sporadic Associations with Rare Diseases Future Directions References Chapter 14: Genetics of Carotid Atherosclerosis Epidemiology Methods of Carotid Measurement and Research Techniques Carotid Plaque Burden Genome-Wide Association Studies (GWAS) Gene Expression Carotid Intimal-Medial Thickness GWAS Candidate Genes Stroke Due to Large Artery Disease GWAS Gene Expression Biomarkers and Polygenic Risk Scores Shared Genetics with Coronary Artery Disease Individual Genes Implicated in Carotid Atherosclerosis 9p21 HDAC9 MMP12 Leukotriene Pathway APOE TSPAN2 PTCSC3 ITGAM/ITGB2 Omics and Carotid Atherosclerosis Conclusions References Chapter 15: Genetics of Cervical Artery Dissection Introduction Monogenic Disorders and CeAD Vascular Ehlers-Danlos Syndrome Marfan Syndrome Loeys-Dietz Syndrome Other Monogenic Disorders Genetic Predisposition to CeAD Linkage studies Genetic Association Studies Based on Candidate Genes Genome-Wide Association Studies References Chapter 16: Stroke Genetics in China Introduction: Epidemiology and of Global Burden of Disease Stroke in China Race, Genetics and Stroke in China Genetics of Ischemic Strokes in Chinese Cohorts Genetics of Hemorrhagic Strokes in Chinese Cohorts Conclusion References Chapter 17: Stroke Pharmacogenetics Introduction Lipid-Lowering Therapy Clinical Efficacy: Pharmacokinetic Factors Determining Variability (Table 17.1) Cytochrome P450 Enzymes CYP3A4 Peroxisome Proliferator-Activated Receptor-α (PPARA) CYP3A5 CYP2D6 Adenosine Triphosphate (ATP)-Dependent Efflux Pumps Pharmacodynamic Factors Determining Variability Adenosine Triphosphate (ATP)-Dependent Efflux Pumps 7 α-Hydroxylase Apolipoprotein E Cholesteryl Ester Transfer Protein (CETP) HMG-CoA Reductase Enzyme Low-Density Lipoprotein Receptor (LDLR) Pleiotropic Effects Toll-Like Receptor 4 (TLR4) Kinesin-Like Protein 6 (KIF6) Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Genome-Wide Association Studies (GWASs) Statin-Related Myopathy Pharmacokinetic Factors Determining Myopathy Risk Cytochrome P450 Enzymes ATP-Binding Cassette G2 Efflux Transporter (ABCG2) SLCO1B1 Pharmacodynamic Factors Determining Myopathy Risk Coenzyme Q10 Genome-Wide Association Studies Clinical Implications Antihypertensive Agents Angiotensin-Converting Enzyme (ACE) Inhibitors Pharmacokinetic Factors Determining Response to ACE Inhibitors Pharmacodynamic Factors Determining Response to ACE Inhibitors ACE Inhibitor-Induced Angioedema and Cough Angiotensin-II Receptor Blockers (ARBs) Beta(β)-Blockers Pharmacokinetic Factors Determining Response to β-Blockers CYP2D6 and UGT1A1 Pharmacodynamic Factors Determining Response to β-Blockers ADRB1 Genome-Wide Association Studies Calcium-Channel Blockers (CCBs) Pharmacokinetic Factors Determining Response to Calcium-Channel Blockers CYP3A4 Pharmacodynamic Factors Determining Response to Calcium-Channel Blockers Genome-Wide Association Studies Thiazide Diuretics Pharmacokinetic Factors Determining Response to Thiazide Diuretics Pharmacodynamic Factors Determining Response to Thiazide Diuretics WNK1 Genome-Wide Association Studies Clinical Implications Antiplatelet Therapy: Aspirin and Clopidogrel Platelet Function Aspirin Aspirin: Licensed Indications Aspirin Resistance Genetic Determinants of Aspirin Response Pharmacokinetic Factors Determining Variability UDP-Glucuronosyltransferase (UGT) Pharmacodynamic Factors Determining Variability COX-1 and COX-2 Platelet Receptors P2Y1 and P2Y2 and GPV1/GP IIIa Genome-Wide Association Studies Clinical Implications Clopidogrel Clopidogrel in the Treatment of Cardiovascular and Cerebrovascular Disease Clopidogrel Nonresponse Genetic Determinants of Clopidogrel Response Pharmacokinetic Factors Determining Variability CYP2C19 PON1 CES1 Genome-Wide Association Studies Clinical Implications Clopidogrel Dose Increase Next-Generation Anti-platelet Agents Oral Anticoagulants Warfarin Pharmacology Pharmacokinetic Factors Determining Warfarin Response Orosomucoid 1 Gene [ORM1] and Orosomucoid 2 Gene [ORM2] CYP2C9 Time to Achieve Stable INR Bleeding Pharmacodynamic Factors Determining Warfarin Response VKORC1 CYP4F2 Other Genes Implicated Clinical Implications Direct Oral Anticoagulants Conclusions Appendix References Further Reading Chapter 18: Cerebral Venous Thrombosis: Genetic Aspects Introduction Predisposing Genes for CVT. General Aspects and Methodological Issues Genetic Diseases Associated with a Higher Risk of CVT Genetic Thrombophilic Diseases Mutations and Polymorphisms in Coagulation Proteins Prothrombin Mutations Factor V Leiden Mutation Polymorphisms in Other Coagulation Proteins Mutations in Natural Anticoagulants Protein C Deficiency Protein S Deficiency Antithrombin Deficiency Protein Z Polymorphisms Polymorphisms in the Fibrinolytic System Genetic Hyperhomocysteinemia Other Genetic Diseases Sickle Cell Disease Genes That Increase the Risk of CVT in Systemic Diseases Recommendations for Genetic Studies in CVT References Chapter 19: Multi-Omics Approaches to Discovering Acute Stroke Injury and Recovery Mechanisms Rationale for a Reverse Translational Approach to Acute Stroke Injury and Recovery Mechanisms Endophenotypes as a Window into Biologic Mechanisms of Injury and Recovery Acute Clinical Phenotypes Stroke Recovery Radiologic Endophenotypes Multi-Omics Approaches Proteomics Transcriptomics Epigenomics Amplifying Cohorts and Phenotyping Through International Collaboration Novel Genetic Approaches to Stroke Injury and Recovery Conclusion References Chapter 20: Genetic Research and the Law Introduction Genetic Privacy Genetic Discrimination Genetic Commercialization Conclusions References Chapter 21: Diagnosis, Investigation, Treatment and Management of Young Stroke in Clinic Introduction Epidemiology Stroke Symptoms Awareness and Recognition Stroke Etiology and Evaluation Genetic Diseases Associated with Stroke Genetic Risk and Precision Medicine Treatment and Management References Index