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Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in Human Cardiovascular Disease.

Aims
We have shown that 14q32 microRNAs are highly involved in vascular remodeling 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 & Results
We performed a look-up of the 14q32 region within the dataset of a Genome Wide Association Scan (GWAS) 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 venae saphenae magnae (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were upregulated. SNORD113.2, which showed a 17-fold upregulation in failed bypasses, was also upregulated twofold in plasma samples drawn from patients with ST-Elevation Myocardial Infarction (STEMI) directly after hospitalization compared to 30 days after start of treatment. Fitting with the genomic associations however, 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.


Conclusions
14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is upregulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.