Clinical epigenomics for cardiovascular disease: Diagnostics and therapies

https://doi.org/10.1016/j.yjmcc.2021.01.011Get rights and content

Highlights

  • Changes in epigenetic features have been measured in blood and cardiovascular tissues in human disease

  • Epigenetic changes can serve as powerful biomarkers of human cardiovascular health and disease

  • Validation of epigenetic biomarkers comes from cohort studies in humans as well as preclinical studies in animals

  • Data acquisition, analysis and integration with medical records are evolving areas necessary for clinical implementation

  • Data sovereignty, clinical education, and machine learning are key opportunities to bridge discoveries to the clinic

Abstract

The study of epigenomics has advanced in recent years to span the regulation of a single genetic locus to the structure and orientation of entire chromosomes within the nucleus. In this review, we focus on the challenges and opportunities of clinical epigenomics in cardiovascular disease. As an integrator of genetic and environmental inputs, and because of advances in measurement techniques that are highly reproducible and provide sequence information, the epigenome is a rich source of potential biosignatures of cardiovascular health and disease. Most of the studies to date have focused on the latter, and herein we discuss observations on epigenomic changes in human cardiovascular disease, examining the role of protein modifiers of chromatin, noncoding RNAs and DNA modification. We provide an overview of cardiovascular epigenomics, discussing the challenges of data sovereignty, data analysis, doctor-patient ethics and innovations necessary to implement precision health.

Introduction

Widespread clinical implementation of precision medicine has the potential to revolutionize clinical care as well as to unleash a myriad of privacy, cost and ethical issues. At present, we are in the early stages of integrating epigenetics into this story—where we end up will depend on appropriate research, stewardship and implementation.

Exact definitions vary but a key feature of precision medicine is the tailoring of clinical care based on an integrated patient history that includes genomic and/or epigenomic data. The power and potential of such strategy could have far reaching effects in patient care. Ideally, precision medicine would be accomplished through a multi-omics approach taking into account individual variability in the genome, epigenome, transcriptome, proteome and metabolome to optimally direct clinical care for each individual. An advantage of epigenetic measurements is that they reflect heritable factors (i.e. DNA sequence), while at the same time being dynamic and thus capable of incorporating environmental factors, which are of critical importance in the pathophysiology of disease.

Heart disease is the leading cause of death for both men and women, as well as across most racial and ethnic groups in the United States. In 2017, there were 859,125 deaths due to cardiovascular disease in the United States [1]. In addition, the total indirect and direct cost of cardiovascular disease in the United States was approximately $351.2 billion for 2014 to 2015 [1]. The implementation of clinical epigenomics in the prevention and management of cardiovascular disease has the potential for significant improvement in patient outcomes. In this review, we will outline the field of epigenomics, recent epigenomics studies in cardiovascular disease, measurement of epigenetic marks, data analysis and challenges to clinical implementation.

Section snippets

Overview of epigenetics

Epigenetic modifications can be considered anything that alters gene function without altering DNA sequence [2]. This includes modifications to the DNA itself, such as methylation [3], in addition to a cadre of proteins that directly bind DNA, such as histones and non-nucleosomal chromatin structural proteins [2].

Histone modification influences chromatin accessibility and the binding and activity of transcriptional machinery [4,5]. These modifications primarily include histone acetylation,

Atherosclerosis

Atherosclerosis is the causative process in peripheral artery disease, coronary artery disease and cerebrovascular disease. Epigenetic modifications have been implicated in the development and progression of atherosclerosis. Increased acetylation of histone H3 lysine 9 (H3K9ac) and histone H3 lysine 27 (H3K27ac) in smooth muscle cells are associated with advanced atherosclerotic lesions compared to healthy carotid arteries [23]. Expression of GCN5L and MYST1 which are regulated by histone

Benefits and challenges in clinical implementation

The clinical implementation of epigenetics has enormous potential, particularly in treating cardiovascular disease. Epigenetic marks can be used to monitor response to treatment of disease and predict therapeutic response. In luminal B breast cancer, DNA methylation has been shown to improve prediction of response to neoadjuvant chemotherapy [98]. DNA methylation has also been shown to be associated with response to etanercept in patients with rheumatoid arthritis [99]. Epigenetics could be

Acknowledgements

The authors thank Elizabeth Soehalim for assistance with the figure. The author as also thankful for support from the Department of Anesthesiology & Perioperative Medicine, the David Geffen School of Medicine and the Clinical and Translational Science Institute (NIH UL1TR000124), all at UCLA.

References (103)

  • H. Cedar

    Linking DNA methylation and histone modification: patterns and paradigms

    Nat Rev Genet

    (2009)
  • A. Jambhekar et al.

    Roles and regulation of histone methylation in animal development

    Nat Rev Mol Cell Biol.

    (2019)
  • Samuel T. Keating

    Epigenetics and metabolism

    Circulation Research

    (2015)
  • W. Zhang et al.

    Epigenetic Modifications in Cardiovascular Aging and Diseases

    Circ Res.

    (2018)
  • T.G. Gillette

    Readers, writers, and erasers: chromatin as the whiteboard of heart disease

    Circ Res.

    (2015)
  • P.A. Jones

    Functions of DNA methylation: islands, start sites, gene bodies and beyond

    Nat Rev Genet

    (2012)
  • J.S. Mattick et al.

    RNA regulation of epigenetic processes

    Bioessays.

    (2009)
  • J.W. Wei et al.

    Non-coding RNAs as regulators in epigenetics

    Oncol Rep.

    (2017)
  • Daniel Holoch

    RNA-mediated epigenetic regulation of gene expression

    Nat Rev Genet

    (2015)
  • I.T. Udo Baron et al.

    DNA methylation analysis as a tool for cell typing

    Epigenetics

    (2006)
  • A.E. Jaffe et al.

    Accounting for cellular heterogeneity is critical in epigenome-wide association studies

    Genome Biol.

    (2014)
  • K.D.S. Hyang-Min Byun et al.

    Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual- specific DNA methylation patterns

    Human Molecular Genetics

    (2009)
  • M.G.N. van Jenny Dongen et al.

    Genetic and environmental influences interact with age and sex in shaping the human methylome

    Nature Commun

    (2016)
  • C.M.R. Jiantao Ma et al.

    Daniel Levy Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality

    Circ Genom Precis Med

    (2020)
  • S.P. Ralf Gilsbach et al.

    Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease

    Nat Commun

    (2014)
  • Ng JW, Wong A, Kuh D, Smith GD, Relton CL, The role of longitudinal cohort studies in epigenetic epidemiology:...
  • C. Goud Alladi et al.

    DNA Methylation as a Biomarker of Treatment Response Variability in Serious Mental Illnesses: A Systematic Review Focused on Bipolar Disorder, Schizophrenia, and Major Depressive Disorder

    Int J Mol Sci.

    (2018)
  • Manuel Rosa-Garrido et al.

    Epigenomes in Cardiovascular Disease

    Circulation Research

    (2018)
  • Y. Asare et al.

    Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability

    Circ Res.

    (2020)
  • M.D.P. Valencia-Morales et al.

    The DNA methylation drift of the atherosclerotic aorta increases with lesion progression

    BMC Med Genomics

    (2015)
  • H.L. Einari Aavik et al.

    Global DNA methylation analysis of human atherosclerotic plaques reveals extensive genomic hypomethylation and reactivation at imprinted locus 14q32 involving induction of a miRNA cluster

    Eur Heart J.

    (2015)
  • J. Ding et al.

    Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease

    Diabetes

    (2015)
  • E.W. Iwona Smolarek et al.

    Global DNA methylation changes in blood of patients with essential hypertension

    Med Sci Monit

    (2010)
  • M.L. Norihiro Kato et al.

    Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    Nat Genet.

    (2015)
  • Julio D. Duarte et al.

    Rhonda M Cooper-Dehoff, Amber L Beitelshees, Kent R Bailey, Roger B Fillingim, Bruce C Kone, Julie A Johnson, Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide

    J Transl Med.

    (2012)
  • AH Association, “About Metabolic Syndrome”....
  • C.F. Luz D Orozco et al.

    Epigenome-wide association in adipose tissue from the METSIM cohort

    Human Molecular Genetics

    (2018)
  • W.A. Al Muftah et al.

    Epigenetic associations of type 2 diabetes and BMI in an Arab population

    Clin Epigenetics

    (2016)
  • T. Rönn et al.

    Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

    Hum Mol Genet.

    (2015)
  • S. Wahl et al.

    Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

    Nature

    (2017)
  • W.H. Organization, Cardiovascular Diseases....
  • D.M. Mathias Rask-Andersen et al.

    Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction

    Human Molecular Genetics

    (2016)
  • G.F. Simonetta Guarrera et al.

    Gene-specific DNA methylation profiles and LINE-1 hypomethylation are associated with myocardial infarction risk

    Clin Epigenetics

    (2015)
  • C.M. Symen Ligthart et al.

    DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

    Genome Biol.

    (2016)
  • M.S. Dan Jiang et al.

    DNA methylation and hydroxymethylation are associated with the degree of coronary atherosclerosis in elderly patients with coronary heart disease

    Life Sci.

    (2019)
  • L. Shen et al.

    Mechanism and function of oxidative reversal of DNA and RNA methylation

    Annu Rev Biochem.

    (2014)
  • Weronica E. Ek et al.

    Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15

    Human Molecular Genetics

    (2016)
  • S.G. Fiorito et al.

    B-vitamins intake, DNA-methylation of One Carbon Metabolism and homocysteine pathway genes and myocardial infarction risk: the EPICOR study

    Nutr Metab Cardiovasc Dis.

    (2014)
  • B.M. Nadezhda Glezeva et al.

    Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes

    (2019)
  • Gilsbach R, Preissl S, et al. , Distinct epigenetic programs regulate cardiac myocyte development and disease in the...
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