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Chapter Summary

This chapter discusses the genetics and epigenetics of cardiovascular disease (CVD) (see Fuster and Hurst’s Central Illustration). Following the advances in deoxyribonucleic acid (DNA) sequencing technologies, our knowledge of cardiovascular genetics and epigenetics has dramatically increased. While we previously understood the genetics of heart disease mainly in the context of syndromic diseases, caused by chromosomal abnormalities, and Mendelian diseases, caused by single-gene defects, we now appreciate the integral roles of noncoding genes, polygenic mechanisms, and epigenetics in mediating heart disease. Herein, we first review conventional genetic mechanisms of heart disease, including chromosomal anomaly-related congenital heart defects and monogenic diseases such as genetic cardiomyopathy, inherited cardiac arrhythmia, and familial hypercholesterolemia. We then discuss the evolving evidence of polygenic mechanisms in heart disease, presenting an example of coronary artery disease and how polygenic risk score is used in its risk stratification. Next, we review epigenetic regulation of gene expression and discuss its role in CVD pathogenesis. Finally, we conclude by discussing a number of emerging technologies, including genome editing technologies, human-induced pluripotent stem cells, and advanced sequencing and bioinformatics technologies, which can further advance our knowledge of genetics and epigenetics of heart disease.

eFig 4-01 Chapter 4: Genomics And Epigenomics of Heart Diseases


A 57-year-old previously healthy man comes to the clinic for newly diagnosed nonischemic cardiomyopathy. He had been found to have severely reduced left ventricular systolic function and began guideline-directed medical therapy. He has no identifiable conventional cardiovascular risk factors. His family history is remarkable for multiple sudden cardiac deaths, premature atrial fibrillation, and heart failure, prompting a clinical genetic screening. His genetic panel identifies a pathogenic variant in Lamin A/C. How does this genetic information affect the management of his condition now and in the future?


Over the past decade, our knowledge of genetics has exponentially increased as a result of advances in DNA sequencing technologies.1 Whereas human genome sequencing initially took more than a decade and billions of dollars to accomplish, the whole human genome can now be sequenced in hours at a remarkably low cost. The advent of next-generation sequencing technology has accelerated genetic research in an unprecedented way,2 allowing the genetic architecture of heart diseases to be gradually unveiled. Previously, the genetics of heart diseases was primarily understood in the context of syndromic diseases from large structural anomalies (eg, trisomy 21) or Mendelian diseases from single nucleotide variations in protein-coding genes. Accumulating research highlights critical roles of noncoding genes in regulating gene expression3 and thereby contributing to disease mechanisms. Additionally, epigenetics, the reversible genetic modifications that regulate gene expression without altering the DNA sequence, has been implicated in various disease processes.4 Here, we first review the basics and select examples of genetic mechanisms of ...

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