Genetic and functional implications of an exonic TRIM55 variant in heart failure

Abstract

<div><h3>Background</h3><p><br></p><p>To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Methods and results</h3><p>Heart failure-associated variants were screened in genotyping array data of the FINRISK study, consisting of 994 cases and 20,118 controls. Based on logistic regression analysis, a potentially damaging variant in <em>TRIM55</em> (rs138811034), encoding an E140K variant, was selected for validations. In HL-1 cardiomyocytes, we used CRISPR/Cas9 technology to introduce the variant in the endogenous locus, and additionally TRIM55 wildtype or E140K was overexpressed from plasmid. Functional responses were profiled using whole-genome RNA sequencing, RT-PCR and Western analyses, cell viability and cell cycle assays and cell surface area measurements. In zebrafish embryos, cardiac contractility was measured using videomicroscopy after CRISPR-mediated knockout of <em>trim55a</em> or plasmid overexpression of TRIM55 WT or E140K. Genes related to muscle contraction and cardiac stress were highly regulated in <em>Trim55</em> E140K/− cardiomyocytes. When compared to the WT/WT cells, the variant cells demonstrated reduced viability, significant hypertrophic response to isoproterenol, p21 protein overexpression and impaired cell cycle progression. In zebrafish embryos, the deletion of <em>trim55a</em> or overexpression of TRIM55 E140K reduced cardiac contractility as compared to embryos with wildtype genotype or overexpression of WT TRIM55, respectively.</p></div><div><h3>Conclusions</h3><p>A previously uncharacterized TRIM55 E140K variant demonstrated a number of functional implications for cardiomyocyte functions <em>in vitro</em> and <em>in vivo.</em> These findings suggest a novel role for <em>TRIM55</em> polymorphism in predisposing to heart failure.</p></div>