Recent Developments in Cardiovascular Genetics
2013; Lippincott Williams & Wilkins; Volume: 113; Issue: 9 Linguagem: Inglês
10.1161/circresaha.113.302634
ISSN1524-4571
Tópico(s)RNA and protein synthesis mechanisms
ResumoHomeCirculation ResearchVol. 113, No. 9Recent Developments in Cardiovascular Genetics Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRecent Developments in Cardiovascular Genetics The Editors The Editors Originally published12 Oct 2013https://doi.org/10.1161/CIRCRESAHA.113.302634Circulation Research. 2013;113:e88–e91The landscape of cardiovascular genetics has changed dramatically during the past 3 decades. These advances might be placed into 2 established and 3 evolving categories. The initial breakthrough came about with the development of the genome-wide map of short tandem repeats or satellite markers.1,2 It ushered in the genetic linkage analysis, mapping the loci of the causal genes and subsequent positioning cloning to identify the causal mutations of single-gene cardiovascular diseases through sequencing of the candidate genes. The approach led to unraveling the molecular genetic causes of various single-gene cardiovascular disorders such as hereditary cardiomyopathies, long-QT syndromes, and others.3–8 The family studies provide the most robust and convincing indication of causality of a variant. However, a significant number of single-gene disorders occur de novo or affect a single or too few individuals to allow robust genetic linkage analysis. Whole-exome sequencing and candidate gene sequencing have often served as the desired approach, and such findings do not adequately indicate causality and require complementation with the functional studies to support the causal role of the variants identified through the sequencing approach.9–12 Overall, this category of genetic discoveries provides more robust evidence for the causality of the variants in the cardiovascular phenotype.The next wave of discoveries came about with the development of the genome-wide map of single nucleotide polymorphisms and the technology for high-throughput genotyping.13,14 These developments made possible to genotype several thousand individuals for ≤2 million single nucleotide polymorphisms and compare the variant frequencies in a large number of cases with the phenotype of interest and controls. The approach, which is referred to as the genome-wide association studies (http://www.genome.gov/gwastudies/), has led to the identification of a large number of loci associated with common complex cardiovascular diseases, such as coronary artery disease, dyslipidemia, and hypertension among others.15–20 Collectively, these discoveries, along with those in the first category, have had a considerable, albeit an imperfect, effect on our understanding of the genetic basis of cardiovascular diseases and have paved the way for the clinical applications of genetic discoveries.The third, less established and a rapidly evolving category is our gradual understanding of the genome biology, defined broadly as functions embedded in the genome beyond those directly resulting from the effects of the DNA sequence variants. Notable among them are the noncoding RNAs, regulatory elements, and chromatin modifications or epigenetics. The recent findings that ≈80% of the genome is transcribed into RNA, including a large number of long noncoding RNAs, have challenged the gene-centric view of the genome.21,22 The Encyclopedia of DNA Elements (ENCODE) project suggests potential regulatory functions of the vast majority of the genomic regions that were previously considered nonfunctional or even junk DNA.21 The ENCODE findings are rather preliminary and diverge from the evolutionary constrain of only ≈15% of the human genome; nevertheless, they have raised considerable interest in the identification and characterization of the regulatory elements in the genome, including long noncoding RNAs.23–26 Similarly, there is an abundance of interest in the role of microRNAs in regulating various biological processes, including the cardiovascular phenotype. In the heart, microRNAs have been implicated in myocyte proliferation,27 reprogramming of nonmyocytes to myocytes,28,29 angiogenesis,30 regulation of gene expression,31,32 valve formation,33 pulmonary arterial hypertension,34 aortic aneurysm,24,35 myocardial ischemic injury,36,37 cardiomyopathy,38–40 cholesterol transport,41 vascular function,42 and others.43–46 Nevertheless, despite the plethora of publications, this initial enthusiasm for noncoding RNAs is likely to give away to robust evidence that substantiates the biological role of a few noncoding RNA beyond being, at best, tweakers and nudgers of the genome management.47Genetic studies do not fully explain the heritable components of the complex trait. Various factors might account for this so-called missing heritability.48 Among them are the epigenetic factors that might be transgenerational. Regardless of their contributions to missing heritability or the lack thereof, epigenetic factors, whether through DNA methylation or through histone modifications of the chromatin, regulate various cardiovascular phenotypes, including development,49 cardiac reprogramming,50–52 angiogenesis and vascular functions,51,53–57 myocardial repair,58 and others.49,56,59,60 Unlike the first 2 categories, the genomic biology is a rapidly evolving field and is likely to continue to expand in the coming years.The fourth category of advances is functional characterization of DNA sequence variants. The conventional approaches of functional characterization of genes have been overexpression and knockout or knockdown studies, which provide valuable insights into gene function.23,61–64 The approaches are extremely powerful in the analysis of a specific gene function.61 Efforts are underway to develop mouse knockout models of all known genes (https://www.komp.org). The findings of the genome-wide association studies, however, do not typically pinpoint a specific gene, let alone the causal gene, but rather to loci, which might contain a large number of genes and certainly a vast number of DNA sequence variants, which mandates functional characterization of a large number of genes and variants. The challenge is further compounded by the presence of large linkage disequilibrium across large segments on the chromosomes, as well as the trans effects of other variants or chromosomal regions.65,66 Furthermore, as stated earlier, the ENCODE findings suggest the presence of a large number of regulatory and putatively functional genomic regions,21 which poses additional challenge in the selection of candidate genes and single nucleotide polymorphisms for functional characterizations. An additional layer of complexity is the inadequateness of in vitro models and model organisms in accurately reflecting the functional significance of the variants in humans.67–69 Nevertheless, the significance of the functional characterization of the DNA sequence variants relates to their potential effects not only on disease susceptibility and clinical outcome, but also on response to pharmacological efficacy and toxicity.20,65,70–73 Thus, there is a considerable focus on high-throughput functional characterization of the large number of variants that have been associated with the clinical phenotypes or are simply present in the genome.Finally, the fifth category relates to linking the genetic variants to the clinical phenotypes. Each genome has 3.2 billion nucleotides and is comprised of ~ 4 million polymorphic sites including 13 500 nonsynonymous variants that differ from the sequence of the reference genome.12,74,75 Advances in high-throughput nucleic acid sequencing have afforded the opportunity to identify these variants in each genome. Yet, at the same time, the high-throughput sequencing of the population genomes has shown the private nature of each genome as evidenced by the presence of a large number of rare and population-specific variants.76,77 To some degree, the clinical effects of the variants relate to their population frequencies because those that are rare are more likely to exert large effects than the common variants.78 Yet, not all rare or uncommon variants have clinically discernible effects, and none of the bioinformatics in silico algorithms are sufficiently robust in identifying the functional variants. With the increasing availability of whole-exome sequencing or whole-genome sequencing, a large number of variants are identified in each exome or genome, further raising the challenge faced by researchers and clinicians in sieving those that are clinically significant from those that are not.79 The complexity is further compounded by the multifarious determinants of the clinical phenotypes, which render one-to-one correlations quite challenging.These 5 categories, while intertwined and not totally independent, will continue to highlight the landscape of the molecular genetic and genomic studies. The technological advances have afforded the opportunity to discover a large number of causal genes and susceptibility loci for cardiovascular diseases and the capability to identify ≈4 million DNS sequence variants in each genome. Yet, the advances have also posed enormous challenges in advancing the discoveries to functional characterization and beyond, to the bedside. One would anticipate that in coming years, these so-called disruptive advances will have considerable influence on the daily care of patients with cardiovascular diseases.Recent Developments in Cardiovascular Research: The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that these Recent Developments articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. —The EditorsFootnotesCorrespondence to [email protected]References1. 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