The genomic architecture of sporadic heart failure

Abstract

Common or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20% and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease-common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies used a candidate gene approach focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data supports risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin-converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene-centric subgenome single nucleotide polymorphism array identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects.

Figure 1. Schematic depiction of epigenetic and genetic mechanisms that may contribute to heart failure

A simple, two-exon (boxes) gene is depicted with 5’ promoter region (to the left of exons) having CpG island and one cis regulatory element, and 3’ untranslated region (to the right of the exons) having a microRNAs binding site. Epigenetic mechanisms (top): Methylation of CG sequences leads to transcriptional silencing. Histone prevents transcription factors (not shown) from interacting with their cis binding elements, but methylation and acetylation of histone weakens its interaction with DNA, enabling transcpription factor binding and activating transcription. MicroRNA binding sites in the 3’ untranslated region recruit transcribed mRNAs to RNA-induced silencing complexes for degradation and translational silencing. Genetic mechanisms (bottom): Sequence variations can alter binding of transcription factors to cis-elements (left), amino acid coding (middle), or preRNA exon splicing (right). Not shown is DNA copy number variations from large genomic deletions.

Figure 2. Postulated effects of common polymorphisms on neurohormonal activation in heart failure

Schematic representation of neurohormonal signaling in heart failure. Myocardial injury in the form of cardiac damage or hemodynamic stress compromises forward cardiac output, activating compensatory increases in renin-angiotensin-aldosterone signaling (RAAS) and catecholamine release from sympathetic nerves. ACE DD genotype increases ACE expression, and CLCNKA Gly83 may prime renin secretion, thus magnifying the RAAS response and causing reactive left ventricular hypertrophy with secondary myocardial impairment. The deletion polymorphism of pre-synaptic α1c adrenergic receptors increases norepinephrine release from sympathetic nerves, and the Arg 389 variant of myocardial β1-adrenergic receptors increases receptor signaling. Both effects sensitize the heart to catecholaminergic toxicity. Opposing these effects is the Leu41 gain-of-function GRK5 polymorphism that accelerates β-receptor desensitization. (Illustration Credit: Cosmocyte/Ben Smith).

Figure 3. Postulated relationship between polymorphism allele frequency and functional consequence on protein coding to cardiomyopathy risk

Benign polymorphisms have little or no functional effect, are not subject to negative selection, and are therefore retained in the population. Mutations with severe functional effects, such as protein truncation or disruption of a critical domain are rare because of purifying selection. Heart failure risk modifiers have modest functional effects that have consequence largely in the context of a second (physical, toxic, hemdynamic, or environmental) injury event.