Implementing genome-driven personalized cardiology in clinical practice

Abstract

Genomics designates the coordinated investigation of a large number of genes in the context of a biological process or disease. It may be long before we attain comprehensive understanding of the genomics of common complex cardiovascular diseases (CVDs) such as inherited cardiomyopathies, valvular diseases, primary arrhythmogenic conditions, congenital heart syndromes, hypercholesterolemia and atherosclerotic heart disease, hypertensive syndromes, and heart failure with preserved/reduced ejection fraction. Nonetheless, as genomics is evolving rapidly, it is constructive to survey now pertinent concepts and breakthroughs. Today, clinical multimodal electronic medical/health records (EMRs/EHRs) incorporating genomic information establish a continuously-learning, vast knowledge-network with seamless cycling between clinical application and research. It can inform insights into specific pathogenetic pathways, guide biomarker-assisted precise diagnoses and individualized treatments, and stratify prognoses. Complex CVDs blend multiple interacting genomic variants, epigenetics, and environmental risk-factors, engendering progressions of multifaceted disease-manifestations, including clinical symptoms and signs. There is no straight-line linkage between genetic cause(s) or causal gene-variant(s) and disease phenotype(s). Because of interactions involving modifier-gene influences, (micro)-environmental, and epigenetic effects, the same variant may actually produce dissimilar abnormalities in different individuals. Implementing genome-driven personalized cardiology in clinical practice reveals that the study of CVDs at the level of molecules and cells can yield crucial clinical benefits. Complementing evidence-based medicine guidelines from large ("one-size fits all") randomized controlled trials, genomics-based personalized or precision cardiology is a most-creditable paradigm: It provides customizable approaches to prevent, diagnose, and manage CVDs with treatments directly/precisely aimed at causal defects identified by high-throughput genomic technologies. They encompass stem cell and gene therapies exploiting CRISPR-Cas9-gene-editing, and metabolomic-pharmacogenomic therapeutic modalities, precisely fine-tuned for the individual patient. Following the Human Genome Project, many expected genomics technology to provide imminent solutions to intractable medical problems, including CVDs. This eagerness has reaped some disappointment that advances have not yet materialized to the degree anticipated. Undoubtedly, personalized genetic/genomics testing is an emergent technology that should not be applied without supplementary phenotypic/clinical information: Genotype≠Phenotype. However, forthcoming advances in genomics will naturally build on prior attainments and, combined with insights into relevant epigenetics and environmental factors, can plausibly eradicate intractable CVDs, improving human health and well-being.

Keywords: Biomarkers; Genome sequencing; Genome-& phenome-wide association studies (GWAS/PheWAS); Genomic decoding of phenotypic diversity; Hemodynamics & myocardial mechanics phenome; Personalized or precision medicine.

Fig 1. Genotype ≠ Phenotype

Cardiological disorders arise from a combination of multiple genomic/genetic, epigenetic, and environmental risk factors interacting in pathogenetic trajectories and leading to a progression in time of multifaceted manifestations of disease, including clinical symptoms and signs. As is shown in the right lower corner panel, there is not a straight-line linkage present between a genetic cause/causal-variant and a particular phenotype. Indeed, because of interactions involving different modifier-gene influences as well as environmental and epigenetic effects, the same etiologic cause may actually produce dissimilar phenotypes/abnormalities in different individuals.

Fig 2

A Breakage, crossover, and recombination of parental chromosomes (M, F) during meiosis results in the generation of chromosomes (C₁, C₂) that share DNA from both parents. The frequency of recombination between alleles of 2 genes depends on the distance between them: genes located close together will have linked (rarely separated) alleles. Accordingly, one nearby allele can be used as a marker for another, and we can utilize SNP markers linked to genetic disease/risk alleles without pinpointing the precise culpable mutation. B Diagram showing all single nucleotide polymorphism (SNP)-trait associations with P-value ≤ 5.0 × 10^-8, mapped onto the human genome by chromosomal locations and displayed on the human karyotype. The Genome-wide Association Studies (GWAS) Catalog is supplied jointly by the National Human Genome Research Institute (NHGRI) and the European Bioinformatics Institute (EMBL-EBI). The diagram is released nightly and available on the NHGRI-EBI Catalog website. Associations are displayed by chromosome and color-coded by class of phenotype. Currently, there are well over 10,000 published genome-wide significant SNP associations, across hundreds of diseases and quantitative traits. The number or letter below each chromosome is its name (1-22, X, Y). Reproduced from Pasipoularides [26], by permission of the Revista Española de Cardiología and the Spanish Society of Cardiology.

Fig 3

A nucleosome is a section of DNA that is wrapped around a core of positively charged proteins called histones that bind the negatively charged DNA and aid in its packaging. Double-stranded DNA loops around 8 histones twice, forming the nucleosome, which is the building block of chromatin packaging. Chromatin forms chromosomes within the nucleus and exists in two forms: euchromatin, is less condensed and can be transcribed; heterochromatin, is highly condensed and is typically not transcribed. There are many ways that gene expression is controlled epigenetically. Adding or removing chemical groups to or from histones can alter gene expression; acetylation and phosphorylation make the histones less positively charged, because acetyl and phosphoryl groups are negative, and their tight hold on DNA becomes looser. Conversely, extensive methylation of cytosine in DNA is correlated with reduced DNA transcription. Adapted from Pasipoularides [83], by permission of the Journal of Cardiovascular Translational Research and Springer US.

Fig 4

Genome-wide association studies (GWAS) involve an examination of a genome-wide set of genetic variants in different individuals to determine if any variant is associated with a particular phenotypic trait; they reveal genetic markers that expand understanding of risks and causes for many diseases, and may guide diagnosis and therapy on a patient-specific basis. Phenome-wide association studies (PheWAS), or “reverse GWAS,” ascertain what clinical disease associations/susceptibilities can be attributed to a single genetic causal variant (a particular genotype). When studied in combination, PheWAS and GWAS can provide new valuable gene–disease pathogenetic insights.

Fig 5

The Circos™ graphics circular ideogram layout facilitates the display of genomic relationships between pairs of positions on the circumference, by the use of linking ribbons, which encode the position, size, and orientation of related genomic elements. In Circos plots, genomic chromosomes are circularly arranged and relationships between genomic regions can be clearly demonstrated by links within the circle, and can reflect any type of correspondence—e.g., defined on the basis of similarity (base sequence or protein), or by category (functional or structural component). If the relationship has an associated quantity, this quantity can be represented by the thickness of the link; by coloring the linking ribbons, tracking relationships to/from an element becomes easier. In this particular Circos™ plot are depicted, clockwise from top right, the genomes of a human, a chimpanzee, a mouse, and a zebrafish, arranged in a circle with each color square corresponding to a pair of chromosomes. The links within the circle connect similar DNA sequences, visually emphasizing just how much DNA humans share with the other 3 species shown. After Krzywinski et al. [22], reproduced with Dr. Krzywinski's permission.

Fig 6

A Deep left ventricular (LVP) and aortic root (AOP) pressures in hypertrophic cardiomyopathy at rest and during supine bicycle exercise, which elicits an abnormal LVP diastolic decay, suggesting impaired ventricular relaxation; LVP decays throughout diastole, in sharp contrast to the normal pattern shown in panel C. B Pressure-flow relationship with large early and enormous mid- and late-systolic dynamic gradients in hypertrophic cardiomyopathy. From top downward: aortic velocity signal, and deep left ventricular (LV), left ventricular outflow tract (LVOT), and aortic root (AO) micromanometric signals, measured by retrograde triple-tip pressure plus velocity multisensor left-heart catheter. Left atrial (LA) micromanometric signal was measured simultaneously by trans-septal catheter. The vertical straight line identifies the onset of SAM-septal contact, determined from a simultaneous M-mode mitral valve echocardiogram (not shown); the majority of aortic ejection flow is already completed by this time. The huge mid- and late- systolic gradient (hatched area) is maintained in the face of minuscule remaining forward or even negative aortic velocities. AO, aortic; AOP, aortic root pressures; LA, left atrial; LV, left ventricular; LVOT, left ventricular outflow tract; LVP, left ventricular pressure; SAM, systolic anterior motion of the mitral valve. Adapted from Pasipoularides [1], with permission of PMPH-USA.

Fig 7

In essence, the DNA editing technique CRISPR/Cas9 works like a biological version of a word-processing program's find-and-replace function. A cell with a defective chromosomal DNA portion is transfected with an enzyme complex containing: a guide-RNA molecule, a DNA-cutting enzyme, and a healthy DNA strand. The specially designed synthetic guide-RNA molecule finds the defective target-DNA strand and a DNA-cutting enzyme (nuclease) then cuts it off, so that it can be subsequently replaced with the healthy DNA strand.

Fig 8

The cholesterol biosynthesis pathway. Cholesterol biosynthesis is a complex process involving more than 30 enzymes. A simplified version is shown here, highlighting the step of mevalonate synthesis, which is inhibited by statins so as to reduce intracellular cholesterol levels; through several interposed steps, these lead to upregulated expression of the LDLR gene. Enhanced LDLR expression increases receptor-mediated endocytosis of LDL and thus lowers serum LDL; the liver produces/contains the most LDL receptors and therefore it removes most LDL from blood. Notable is the adverse side-effect of the attendant impaired synthesis and lowered body's levels of coenzyme Q10, which is important in cellular energy generation processes and as a powerful antioxidant, reducing free radicals that can damage cells and DNA. Taking CoQ10 supplements can help increase CoQ10 levels and may reduce statin side effects.