Clinical epigenomics for cardiovascular disease: Diagnostics and therapies
Graphical abstract
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)
- et al.
Jaroslav Pelisek Histone acetylation and methylation significantly change with severity of atherosclerosis in human carotid plaques
Cardiovascular Pathology
(2016) - et al.
Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study
Lancet Diabetes Endocrinol.
(2015) - et al.
Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure
Lab Invest.
(2019) - et al.
Is Atrial Fibrillation a Preventable Disease?
J Am Coll Cardiol.
(2017) - et al.
Strategies for analyzing bisulfite sequencing data
J Biotechnol.
(2017) - et al.
DNA Methylation Clocks in Aging: Categories, Causes, and Consequences
Mol Cell.
(2018) - et al.
American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee, Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association
Circulation
(2020) The molecular hallmarks of epigenetic control
Nat Rev Genet
(2016)The diverse roles of DNA methylation in mammalian development and disease
Nat Rev Mol Cell Biol.
(2019)Regulation of chromatin by histone modifications
Cell Res
(2011)
Linking DNA methylation and histone modification: patterns and paradigms
Nat Rev Genet
Roles and regulation of histone methylation in animal development
Nat Rev Mol Cell Biol.
Epigenetics and metabolism
Circulation Research
Epigenetic Modifications in Cardiovascular Aging and Diseases
Circ Res.
Readers, writers, and erasers: chromatin as the whiteboard of heart disease
Circ Res.
Functions of DNA methylation: islands, start sites, gene bodies and beyond
Nat Rev Genet
RNA regulation of epigenetic processes
Bioessays.
Non-coding RNAs as regulators in epigenetics
Oncol Rep.
RNA-mediated epigenetic regulation of gene expression
Nat Rev Genet
DNA methylation analysis as a tool for cell typing
Epigenetics
Accounting for cellular heterogeneity is critical in epigenome-wide association studies
Genome Biol.
Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual- specific DNA methylation patterns
Human Molecular Genetics
Genetic and environmental influences interact with age and sex in shaping the human methylome
Nature Commun
Daniel Levy Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality
Circ Genom Precis Med
Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease
Nat Commun
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.
Epigenomes in Cardiovascular Disease
Circulation Research
Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability
Circ Res.
The DNA methylation drift of the atherosclerotic aorta increases with lesion progression
BMC Med Genomics
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.
Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease
Diabetes
Global DNA methylation changes in blood of patients with essential hypertension
Med Sci Monit
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
Nat Genet.
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.
Epigenome-wide association in adipose tissue from the METSIM cohort
Human Molecular Genetics
Epigenetic associations of type 2 diabetes and BMI in an Arab population
Clin Epigenetics
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.
Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
Nature
Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction
Human Molecular Genetics
Gene-specific DNA methylation profiles and LINE-1 hypomethylation are associated with myocardial infarction risk
Clin Epigenetics
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases
Genome Biol.
DNA methylation and hydroxymethylation are associated with the degree of coronary atherosclerosis in elderly patients with coronary heart disease
Life Sci.
Mechanism and function of oxidative reversal of DNA and RNA methylation
Annu Rev Biochem.
Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15
Human Molecular Genetics
B-vitamins intake, DNA-methylation of One Carbon Metabolism and homocysteine pathway genes and myocardial infarction risk: the EPICOR study
Nutr Metab Cardiovasc Dis.
Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes
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