Understanding cardiovascular disease: a journey through the genome (and what we found there)

Abstract

Cardiovascular disease (CVD) is a major cause of mortality and hospitalization worldwide. Several risk factors have been identified that are strongly associated with the development of CVD. However, these explain only a fraction of cases, and the focus of research into the causes underlying the unexplained risk has shifted first to genetics and more recently to genomics. A genetic contribution to CVD has long been recognized; however, with the exception of certain conditions that show Mendelian inheritance, it has proved more challenging than anticipated to identify the precise genomic components responsible for the development of CVD. Genome-wide association studies (GWAS) have provided information about specific genetic variations associated with disease, but these are only now beginning to reveal the underlying molecular mechanisms. To fully understand the biological implications of these associations, we need to relate them to the exquisite, multilayered regulation of protein expression, which includes chromatin remodeling, regulatory elements, microRNAs and alternative splicing. Understanding how the information contained in the DNA relates to the operation of these regulatory layers will allow us not only to better predict the development of CVD but also to develop more effective therapies.

Fig. 1.

Gene activity is controlled by multiple layers of regulation. For RNA to be transcribed, chromatin needs to be unwound so that genes can be accessed by the transcription machinery. Chromatin remodeling is controlled by methylation (Me) and acetylation (Ac) marks on histones that determine how open or closed the chromatin is. Activation of gene transcription is also controlled by enhancer regulatory elements that can sometimes be several kilobases away. Once transcribed, the immature mRNA (pre-mRNA) undergoes splicing to remove introns. The inclusion or exclusion of an exon is subject to variation (alternative splicing), which can generate multiple protein isoforms from a single gene. Splicing regulators are often alternatively spliced themselves (represented by curved arrow). mRNA translation is regulated by a range of non-coding RNAs (ncRNAs), including microRNAs. Some ncRNAs, such as ceRNAs, can regulate the activity of microRNAs (represented by curved arrow). These multiple layers of regulation interact with each other; for instance, chromatin modification and microRNAs both modulate alternative splicing, and ncRNAs can also act as transcriptional enhancers to promote transcription. The different regulatory mechanisms respond to pathological stimuli by changing both the amounts and the isoforms of the multiple proteins that are involved in tissue homeostasis and the development of CVD. Further investigations will determine the potential of each of these layers to be targeted therapeutically.

Fig. 2.

Future trends in predicting the risk of CVD. The need to predict the risk of CVD is undeniable. The Framingham Heart Study defined a set of risk factors (represented by blue line) that has been the gold standard since the 1960s. However, these classical risk factors only predict a fraction of CVD. Although large-scale genetic analyses have identified hundreds of risk-associated common sequence variants (green line), these have added little or no additional predictive value to the classical risk score. However, this trend is set to change in the near future, as additional common variants and novel rare variants are identified. Furthermore, once we gain a better understanding of how genes and gene variants interact with each other and with environmental and behavioral factors, a synergistic effect can be expected, and thus our ability to predict CVD before the appearance of symptoms will greatly increase (red line).