Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease

Abstract

Aims We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 ‘orphan’ small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease. Methods and results We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice. Conclusion 14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.

A role for m6A RNA methylation in heart failure development?

“…Multiple other forms of RNA methylation have been uncovered. We have recently shown that changes in a specific set of small nucleolar RNAs that guide 2'O‐ribose methylation of RNA associate with heart failure in human …”

Plasma Levels of snoRNAs are Associated with Platelet Activation in Patients with Peripheral Artery Disease

“…However, microRNAs are not the only small ribonucleic acids (RNAs) that display such favourable properties for biomarkers. We recently showed that a set of small nucleolar RNAs (snoRNAs) had potential as biomarkers for muscle damage and repair in elite athletes and end stage PAD patients [9], as well as for the recovery of patients with ST-elevation myocardial infarction (STEMI) that underwent percutaneous coronary intervention (PCI) [10]. SnoRNAs are also small RNA molecules that are between 60 and 300 nucleotides in length and play an important role in cellular machinery.…”

“…We selected snoRNAs that showed significant overexpression in the plasma of end-stage PAD patients compared to healthy individuals in a previous study [9]. All four snoRNAs are transcribed from the 14q32 locus, a noncoding RNA gene locus that is strongly linked to human cardiovascular disease, including PAD and restenosis [10,12,13,14,15,16]. We aimed to evaluate the associations between snoRNA plasma levels with restenosis, MI and TIA/stroke, but also with classical risk factors for PAD development and progression, including smoking and platelet activation.…”

Cardiovascular Research at the frontier of biomedical science

“…8 Beyond microRNAs, small nucleolar RNAs (snoRNAs) such as 14q32 snoRNAs, encoded by the same locus as microRNAs suspected to be involved in vascular remodelling and cardiovascular disease, have now been proposed to have an independent role in cardiovascular pathophysiology. 9 Another example of the far-reaching influence of non-coding RNAs in cardiac pathologies, recently published in Cardiovascular Research, compared human cardiac long non-coding RNA (lncRNA) profiles in controls and patients with dilated cardiomyopathy (DCM) and hinted at the diverse functional roles of these molecules in different heart cell types. 10 Furthermore, it has emerged that the lncRNA TUG1, already implicated in atherosclerosis, may have additional functions in regulating osteogenic differentiation in calcific aortic valve disease.…”