RiboSNitches as biomarkers in complex cardiovascular diseases

Basic data for this project

Description

We intend to identify novel lncRNA-based biomarkers, designated “riboSNitches”, implicated in the etiology of complex cardiovascular diseases. A riboSNitch is an element of RNA structure with a specific function that is disrupted by a nucleotide variant. Despite considerable efforts in genome-wide association studies (GWAS), the genetic heritability of complex diseases is only partly explained by common variants in coding genes. Furthermore, a significant proportion of the association signals is located in non-coding regions of the genome, shifting the focus to the contribution of non-coding RNAs. Particularly long non-coding RNAs (lncRNAs) have been shown to affect epigenetic gene regulation in multiple ways and play an essential role in etiology of dilated cardiomyopathy (DCM), coronary artery disease (CAD) and myocardial infarction (MI). By sequencing DNA samples of DCM patients complemented by next generation sequencing data already generated from a CAD cohort, we aim to identify new genomic variants in lncRNAs possibly affecting the secondary structure and thereby the function of these versatile regulatory molecules. To estimate the impact of a variant we will predict the resulting secondary lncRNA structure by established algorithms based on thermodynamic parameters in-silico. The predicted conformational changes of high impact variants will be validated experimentally by SHAPE-Seq chemical probing in-vitro. A subset of validated high-impact variants will be genotyped in large cohorts of DCM, CAD and MI and subsequently analyzed for their potential contribution to the genetic variance underlying the respective disease. The functional effects of the associated lncRNAs on gene expression will be investigated utilizing public lncRNA databases and a set of transcriptomic and epigenomic data already available for our CAD cohort.