Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions

Abstract

A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the "post-genomic" era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how "modifier genes" influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many-practitioners and investigators-to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

Keywords: Environmental influences and epigenetics; Exons, introns, and alternative splicing; Gene interactions and epistasis; Genetic cardiomyopathies, HCM, DCM; Genotype and expressed phenotypes; Major gene, “modifier genes,” and pleiotropy; Monogenic and polygenic traits and gene networks; Mutations and haplotypes; Regulatory DNA “switches” and regulation of gene expression.

Fig. 1

Alternative splicing (AS) comprises mechanisms that enable a single gene to splice its mRNA transcripts in multiple ways, thus creating an assortment of dissimilarly spliced mRNA species, polypeptides, and proteins. Alternative splicing can allow one gene to generate different proteins (see protein isoforms discussion in text) in diverse tissues. Consequently, diversity encoded within the genome and organismal complexity can increase greatly without increasing the genome size. The human genome contains around 20,000–25,000 genes, substantially fewer than the 90,000 distinct proteins that are estimated to be assembled. Constitutive splicing (depicted in the top panel) means that all exons are joined together in the order in which they occur in the precursor mRNA (pre-mRNA) that is synthesized from a DNA template in the nucleus by transcription. Alternative splicing also occurs in the nucleus and entails various mechanisms that can alter the resulting mRNA products in several ways (exemplified in the lower panels) including exon skipping, mutually exclusive exons, and the use of alternative splice donor or acceptor sites. Certain such alterations in gene expression can result in disease states

Fig. 2

A static gene-to-gene interaction network summary map around five selected query genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1) implicated in genetic HCM—cf., Table 1 and discussion in text. The query genes are highlighted in yellow; the network displayed includes only the strongest links between the non-query subnetwork genes. Prepared using FunCoup, v. 3.0 build 2014–02; the name stands for functional coupling. FunCoup, developed by the Science for Life Laboratory of the Karolinska Institutet of Sweden, is a framework to infer genome-wide functional couplings in 11 model organisms, including the human. Functional coupling is an unspecific form of association that encompasses direct physical interaction but also more general types of direct or indirect interaction like regulatory interaction or participation in a normal or disease process (Color figure online)

Fig. 3

Some gene action patterns operative in determining phenotypic traits. a In a monogenic one-to-one pattern, a single gene determines a particular phenotype or trait. b In a monogenic one-to-many configuration, a single gene determines/affects a number of different phenotypes or traits and each of the latter is determined/influenced by that single gene. This is a manifestation of pleiotropy, or the phenomenon in which a single gene contributes to multiple apparently unrelated phenotypic traits. c In a many-to-one arrangement, a particular phenotype or trait embodies the actions of several genes, which may encompass a primary gene and assorted modifier genes. d In a many-to-many action pattern, each gene determines/influences several phenotypes/traits and each of the latter embodies the actions of several genes

Fig. 4

a Solid-state, multisensor left heart catheterization in dilated cardiomyopathy (DCM) at rest (top) and during supine bicycle exercise (bottom). Notable both at rest and during exercise are the elevated LV filling pressures and the more rounded and symmetric than normal transaortic pressure gradients and ejection flow waveforms, reflecting reduced upstroke slopes in the aortic root flow signals with prolonged times to peak flow and increased downstroke steepness—there is both a depressed rate of ejection velocity increase and an enhanced rate of velocity falloff. The very rapid downstroke of the ejection waveform, especially during exercise, probably reflects a high wall stress level maintained throughout ejection and the operation of the inverse force-velocity relation [2, 82, 93, 96]; the normal swift decrease in wall stress that accrues from wall thickening and radial contraction (a ventricular “self-unloading”) is restrained in DCM. b (top panels) Left heart catheterization (similar to (a)) in hypertrophic cardiomyopathy (HCM); deep LVP and AOP signals demonstrate very large early and enormous mid and late systolic dynamic transvalvular pressure gradients. Severe diastolic dysfunction in HCM is also revealed by the micromanometric catheter during supine ergometer cycle exercise; particularly striking is the persistently downsloping micromanometric LVP throughout the diastolic period and up to the ensuing atrial contraction, suggesting greatly impaired ventricular relaxation. This is in sharp contrast to the exercise-induced sharp upslope of diastolic micromanometric LVP in the normal pattern, shown in (c). b (bottom panel) From top downward are shown: linear AO flow velocity signal and AOP, deep LVP, and LVOTP micromanometric signals measured by retrograde triple-tip pressure plus velocity multisensor left heart catheter; the LAP micromanometric signal is measured by transseptal catheter. Inertial forces associated with local and convective accelerations of intraventricular blood dominate the early phase of ejection. This phase is characterized by increasing deep and outflow tract left ventricular and aortic root pressures, while aortic root flow velocity briskly attains and transiently remains near its peak. It is the interaction of flow-field geometry, namely, outflow tract narrowing by massive subaortic septal hypertrophy, with enhanced early velocities and accelerations that underlies the augmentation of the multisensor micromanometric catheter-derived early ejection pressure gradients. Viscous effects grow rapidly with shrinking cavity size. Augmented convective acceleration forces, associated with wall collapse displacing a sequentially increasing blood volume from apex to aortic ring and necessitating a strong increase in velocity along the outflow axis independently of any coexisting geometric taper, and viscous shear forces readily account for the enormous mid and late systolic intraventricular pressure gradients [2, 82, 98]. AO: aortic; LV: left ventricular; LVOT: left ventricular outflow tract; LA: left atrial. ((a) is slightly modified from Pasipoularides [82], with permission of the American College of Cardiology; (b) and (c) are adapted and modified, with permission of PMPH-USA, from Pasipoularides [2].)

Fig. 5

Illustrated is genomic DNA packed tightly into chromosomes, as well as a DNA molecule unwound to reveal its 3D structure, along with epigenetic modifiers. Epigenetics translates into “superposed on the genome.” So, if the genome is like the hardware of a computer, the epigenome would represent the software that instructs the computer when to work, how to work, and how much. Epigenetic mechanisms allow cells carrying identical DNA to differentiate into numerous cell types, and to maintain differentiated—and highly adaptable to their changing “environment”—cellular states. Epigenetics thus forms a bridge between the genotype and the exhibited normal and abnormal/diseased phenotypes. Epigenetic modifications encompass, among others, histone modifications such as acetylation (1) and DNA methylation (2), which regulate gene expression. Standard variant genetic mechanisms (3) are linked to changes in the primary DNA sequence occasioning more or less severe abnormal morphomechanical traits. DNA cytosine methylation and histone modifications have profound roles in gene regulation; the two mechanisms cooperate in controlling gene expression. In contrast to genetic changes that are specific, epigenetic modifications of gene expression are more general and usually involve more than one gene. Complex diseases, such as genetic cardiomyopathies (e.g., HCM and DCM) that are conventionally classified as “monogenic” are most likely caused by causal variants with large effect sizes acting in conjunction with “modifier genes.” In addition to the main causal variant, e.g., MYH7, which typically displays a Mendelian pattern of inheritance, several other non-Mendelian variants contribute to each of the divergent phenotypes that can be actually expressed (HCM or DCM, see discussion in text)