The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association

Abstract

Abstract-There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias. (Circ Cardiovasc Genet. 2017;10:e000037. DOI: 10.1161/HCG.0000000000000037.)Key Words: AHA Scientific Statements ◼ cardiovascular diseases ◼ DNA ◼ epigenomics ◼ genome ◼ metabolomics ◼ proteomics ◼ strokeThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 13, 2017, and the American Heart Association Executive Committee on April 17, 2017. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The American Heart Association requests that this document be cited as follows: Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the "Copyright Permissions Request Form" appears on the right side of the page. I n no small part as a result of the completion of the Human Genome Project, considerable effort has been invested over the past few decades in understanding the contribution of genetics to the risk of cardiovascular diseases and stroke. Genomewide association studies, candidate gene sequencing studies, a...

Transcriptome Profiling in Systems Vascular Medicine

“…From these studies, readers can also mine data according to web-based instructions, and develop a working hypothesis to test whether gene X is involved in the development and progression of vascular diseases. Due to the complex nature of transcriptional regulation, the level of specific transcripts is determined by both transcriptional machinery and environment (such as diet, nutrient etc) ( Musunuru et al, 2017 ). Together with recently emergence of single cell RNA-seq ( Linnarsson and Teichmann, 2016 ), these biotechnological advances will provide powerful toolboxes for understanding the vascular transcriptome and represent an import step toward precision cardiovascular medicine.…”

“…It is more sensitive in detecting very lowly expressed genes or extremely highly expressed genes, therefore, offers a wider dynamic range than traditional microarray ( Zhao et al, 2014 ). It is replacing microarray and thus becoming the predominant tool for transcriptome studies in basic, translational and clinical research ( Musunuru et al, 2017 ). Noteworthy, RNA-seq is also a powerful tool for investigating non-coding RNA, lncRNAs in particular [such as SMILR ( Ballantyne et al, 2016 ), MANTIS ( Leisegang et al, 2017 ), LincRNA-p21 ( Wu et al, 2014 ), Lnc-Ang362 ( Leung et al, 2013 ), MYOSLID ( Zhao et al, 2016 ), RNCR3 ( Shan et al, 2016 )], regulates many facets of vascular biology (reviewed in Li et al, 2016 ; Poller et al, 2017 ), demystifying the “dark” genome of vascular diseases.…”

“…Transcriptomic comparisons would facilitate the identification of differentially expressed transcripts between human diseased and control samples, in different vascular cell types (endothelial cells, monocytes/macrophages, and smooth muscle cells), or in response to different pharmacological/genetic/environmental perturbations ( Musunuru et al, 2017 ). Three common types of transcriptome profiling in vascular biology are summarized as below ( Tables 3 – 5 ):…”

“…However, the value of these transcriptomic data was always underestimated since most of the deposited data are not released to public until manuscripts are published. Therefore, it is critical to make large-scale efforts to mine, validate, and integrate the underlying information streams arising from various transcriptomics studies ( Musunuru et al, 2017 ). To meet the increasing need of precision medicine, AHA has recently established the Institute for Precision Cardiovascular Medicine 1 , offering a new category of data-mining grants focused on harmonizing and mining CVD-based data for cardiovascular therapeutics.…”

Precision Medicine in Non-Communicable Diseases

“…HLA-C*06:02-negative patients respond better to adalimumab than ustekinumab [36,37]. Other examples of NCDs which involve the use of GB for diagnosis or choice of therapy include cardiovascular disorders, diabetes, Parkinson's disease, age-related macular degeneration, inflammatory bowel diseases, autism spectrum disorder, and schizophrenia (Table 1) [38][39][40][41][42][43][44]. These examples are set to increase in the coming years according to the discovery of rare alleles [45].…”