Front Cover

Genomic and Precision Medicine

Copyright Page

Contents

List of Contributors

1 Family Health History and Health Risk Assessment For Cardiovascular Disease in Health Care

Introduction

In the Beginning

Why Family Health History is Central to HRAs

An Implementation Crisis

Will Providers Use It?

Will the Patients Use It?

What About Patient-Entered Data?

Does It Make a Difference?

Conclusion

References

2 Personalized Lifestyle Medicine

Introduction

Elements of a Lifestyle Medical Program

Dose Effects

Lifestyle Pharmacology

Lifestyle Medicogenetics

Genetic Determinants of Variable Responses

Personalized Lifestyle Medicine—the Right Therapy, for the Right Person, at the Right Time

The Interactions of Lifestyle Medicine, Genetics, and Pharmacotherapy

References

Further Reading

3 Lipoprotein Disorders

Introduction

Overview of Lipoprotein Metabolism

Genomics of Plasma Lipids

Mendelian Disorders of Lipoprotein Metabolism

Mendelian Disorders Causing Elevated Triglyceride Levels

Familial Chylomicronemia Syndrome (FCS)

Familial Dysbetalipoproteinemia

Mendelian Disorders Causing Elevated LDL-C Levels

Familial Hypercholesterolemia

Autosomal Recessive Hypercholesterolemia and Sitosterolemia

Mendelian Conditions Causing Reduced LDL-C Levels

Abetalipoproteinemia

Familial Hypobetalipoproteinemia

PCSK9 Deficiency

Familial Combined Hypolipidemia (ANGPTL3 Deficiency)

Mendelian Conditions Causing Extreme HDL-C Levels

Single-Gene Causes of Extremely Low HDL-C

Single-Gene Causes of Extremely High HDL-C

Variants in Lipid-Associated Genes and their Relationship to Cardiovascular Disease

LDL-C Variants and CAD

TG Variants and CAD

HDL-C Variants and CAD

Summary and Future Directions

References

4 Metabolic Syndrome

Introduction

Defining Metabolic Syndrome

Pathophysiology of Metabolic Syndrome

Heritability of Metabolic Syndrome

Monogenic Models of Metabolic Syndrome

Lipodystrophy

Monogenic Diseases of Obesity and Insulin Resistance

Genetics of Common Metabolic Syndrome

Linkage Analysis

Candidate Gene-Association Studies

Genome-Wide Association Studies

Risk-Score Analysis

Finding the Missing Heritability

The “Thrifty-Gene” Hypothesis

Clinical Implications to Genetic Findings in Metabolic Syndrome

Conclusion

Acknowledgments

References

5 Hypertension

Introduction

Blood Pressure Gene Discovery

Large-Scale European GWAS Metaanalyses

GWAS of Non-European Ancestries

Candidate Gene Studies

Longitudinal Data, Gene–Lifestyle Interactions, and Multitrait Analyses

Bespoke Genotyping Arrays

Rare Genetic Variants and BP

New BP Genes and Molecular Mechanisms

BP Variants and Association with Other Traits and Outcomes

Conclusion

Acknowledgments

References

6 Novel Approaches to Cardiovascular Diagnostics: Focus on Coronary Artery Disease and Myocardial Infarction

Introduction

What’s New?

Clinical Challenges

Genetics

Transcriptomics

Methodology

Gene Discovery for CAD

Clinically Validated Gene Expression Tests for Obstructive CAD

Corus CAD Analytical Validation

Corus CAD Clinical Validation

Gene Discovery for MI Signatures

Multivariate Proteomic Predictors of CAD and MACE

Proteomic Predictors of CAD

Proteomic Predictors of MACE

Multimodality or Systems Biology Approaches

Other Approaches

Conclusion

References

7 Hypertrophic Cardiomyopathy in the Era of Genomic Medicine

Definitions, Clinical Presentation, and Diagnosis

Introduction

Clinical Presentation and Diagnosis

Echocardiography

Magnetic Resonance Imaging

Molecular Genetics of Hypertrophic Cardiomyopathy

HCM Phenocopies

Role of Modifiers in HCM

Genotype–Phenotype Relationships in HCM

Next Generation Sequencing and Interpretation of the Genetic Test

Screening and Treatment for HCM

HCM Genetic Testing in Clinical Practice

Follow-up and Sports Participation

Pharmacological Therapy for (Obstructive) HCM

Pharmacogenomics

Septal Reduction Therapies for the Treatment of Obstructive HCM Refractory to Pharmacotherapy

Septal Myectomy Surgery

Septal Ablation

Implantable Cardioverter-Defibrillator

Conclusions

References

Further reading

8 Genomics to Predict Risk of Coronary Artery Disease

Introduction

Genome-Wide Association Studies

Identification of Rare Variants

Risk Prediction

Sequencing Families

Conclusion

Acknowledgments

Conflicts of Interest

Funding

References

9 Genomics-Guided Antithrombotic Therapy for Acute Coronary Syndromes

Introduction

Antiplatelet Agents

Aspirin

Therapeutic Implications

P2Y12 Receptor Antagonists

Clopidogrel

CYP2C19

ABCB1

PONI

Therapeutic Implications

Vitamin K Antagonists (Warfarin)

CYP2C9

VKORCI

CYP4F2

Therapeutic Implications

Conclusions

References

10 Heart Failure: Impact of Genetics and Genomics

Part One

Genetic Insight Into the Underpinnings of Heart Failure

Part Two

Impact of Genetics and Genomics on Susceptibility, Diagnosis, Prognosis, and Pharmacogenomics

Susceptibility/Screening

Diagnosis/Prognosis

Pharmacogenomics

β-Blockers

Anticoagulation Therapy

Lp(a) (Lipoprotein a)

Future

References

11 Arrhythmia Genomics

Scope of the Problem

Overview of Cardiac Electrical Activity

From Rare Disease Genetics to Common Arrhythmias: The Long-QT Syndrome Example

Long-QT Syndrome Disease Genes

A Brief Primer in Normal and Abnormal Cardiac Repolarization

Defective Channel Function in cLQTS

Clinical Correlates of LQTS Mutations

Other LQTS Disease Genes and Variants

Genome-Wide Approaches to Studying the QT Interval

Acquired Long-QT Syndrome

Generalizing to Other Familial Arrhythmia Syndromes

From a Common Disease to Genetics: The AF example

AF Mechanisms: Overview

Common and Rare Genetic Variants Associated With AF Risk

Antiarrhythmic Drug Pharmacogenetics

Application of Genomics to Arrhythmia Practice: Current Status and Future Prospects

References

12 Genetics and Genomics of Peripheral Arterial Disease

Introduction

Epidemiology and Risk Factors for PAD

Clinical Manifestations of PAD: A Barrier to PAD Genetics

Therapeutic Strategies for PAD

Genetic Susceptibility in the Causation of PAD

Gene Polymorphisms and Development of PAD

Polymorphism of Proatherothrombotic Genes and PAD

Unbiased Genetic Locus and PAD Susceptibility

Genetic Modifiers of PAD

Refining an Identified QTL Using Haplotype Analysis

Identification of Candidate Genes using Expression Data

Biomarkers of PAD

Future Potential Use of Genomic Methodologies in PAD

References

Further reading

13 Genetic Basis of Congenital Heart Disease

Introduction

Monogenic Causes of Specific Cardiac Malformations

Atrial Septal Defect

Ventricular Septal Defect

Bicuspid Aortic Valve

Supravalvar Aortic Stenosis

Additional Lesions

Copy Number Variation

De Novo Mutations

Common Variants

Noncoding Mutations

Clinical Genetic Evaluation and Testing

Conclusions

Acknowledgment

References

Further Reading

14 Perioperative Genomics

Scientific Rationale for Perioperative Precision Medicine

Perioperative Cardiac Adverse Events

Inflammatory Biomarkers and Perioperative Myocardial Outcomes

Thrombosis Biomarkers and Perioperative Myocardial Outcomes

Natriuretic Peptides and Perioperative Myocardial Outcomes

Genetic Variability Associated With Perioperative Vascular Reactivity and Vasoplegic States

Genome-Wide Association Studies and Perioperative Myocardial Adverse Events

Perioperative Atrial Fibrillation

Postoperative Event-Free Survival

Postoperative Stroke and Cognitive Dysfunction

Perioperative Acute Kidney Injury

Dynamic Genomic Markers of Perioperative Outcomes

Conclusions

Acknowledgments

References

15 Genomics of Ischemic Stroke and Prospects for Clinical Applications

Introduction

Phenotypic Heterogeneity of Stroke

Familial Aggregation of Ischemic Stroke

Monogenic Syndromes that Include Stroke

Genes Associated with Common Forms of Ischemic Stroke

Using Genomewide SNPs to Estimate Stroke Heritability and Genetic Overlap Shared Between Stroke and Other Disorders

Clinical Applications of Genetics in Stroke

Risk Prediction

Screening for Mendelian Disorders

Pharmacogenomics

Conclusion

References

16 Cardiovascular Pharmacogenetics

Pharmacogenetics of HMG-CoA Reductase Inhibitors or “Statins”

Laboratory Response

APOE (Apolipoprotein E)

SLCO1B1 (Solute Carrier Organic Anion Transporter Family, Member 1B1)

LPA (Lipoprotein(a))

SORT1/CELSR2/PSRC1

Musculoskeletal Side Effects

Thienopyridines (Anti-platelet Agents)

Laboratory Response to Clopidogrel

CYP2C219

Clinical Response to Clopidogrel

CYP2C19

Clinical Implications

Warfarin

Laboratory Response to Warfarin

CYP2C9

VKORC1

CYP4F2

Other Loci

Clinical Response to Warfarin

Clinical Implications

Conclusion and Future Directions

References

Glossary

Abbreviations

Index

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