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

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  1. Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse

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  3. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

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  • Kjell E J Håkansson
  • Eveline A C Goossens
  • Stella Trompet
  • Eva van Ingen
  • Margreet R de Vries
  • Reginald V C T van der Kwast
  • Rasmus S Ripa
  • Jens Kastrup
  • Philipp J Hohensinner
  • Christoph Kaun
  • Johann Wojta
  • Stefan Böhringer
  • Saskia le Cessie
  • J Wouter Jukema
  • Paul H A Quax
  • A Yaël Nossent
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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.

Original languageEnglish
JournalCardiovascular Research
Volume115
Issue number10
Pages (from-to)1519-1532
Number of pages14
ISSN0008-6363
DOIs
Publication statusPublished - 1 Jan 2019

Bibliographical note

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.

    Research areas

  • 14q32 locus, Cardiovascular disease, DLK1-DIO3, Non-coding RNA, snoRNA, STEMI, Vascular tissue, Vessels

ID: 56431756