Abstract
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by fibro-fatty myocardial replacement, malignant ventricular arrhythmias and sudden cardiac death. Rare pathogenetic variants in genes encoding desmosomal proteins are well-established causes of ACM. Complementarily to clinical studies, population-based studies offer the possibility to assess whether common variants in selected genes might affect cardiac conduction in the general population.
Methods and results: P-wave, PR, QRS and QT intervals were measured using standard 12-lead electrocardiograms in 4295 genotyped participants of the Cooperative Health Research in South Tyrol (CHRIS) study (data release 2). We tested for possible association with common variants in ACM desmosomal genes. The rs2744389 variant in DSP gene was found to be associated with a shorter QRS interval (beta= -1.10ms, standard error=0.24, p=3.5x10-6). Tissue-specific gene expression data analysis in GTEx database indicates that rs2744389 is linked with expression of the antisense RP3-512B11.3 lncRNA, rather than of DSP gene. A causal effect of lncRNA on QRS was supported by Mendelian Randomization results. Downregulation of lncRNA expression, using a matching sequence GapmeR, in human induced pluripotent stem cell derived cardiomyocytes, led to a significant upregulation of DSP, both at the mRNA (16.39±3.32vs11.84±1.79; p=0.031), and protein level (2.44±0.29vs1.66±0.11; p=0.015).
Conclusions: We have identified an association between a common DSP variant and a shorter QRS interval in a general population sample. In addition, we have highlighted a new mechanism regulating the DSP gene expression through an antisense lncRNA. While warranting further evidence, these findings might indicate a novel possible therapeutic approach for patients affected by ACM, as well as dilated cardiomyopathy, Carvajal syndrome, and some cancer conditions, all caused by DSP mutations leading to a desmoplakin protein reduction.