Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease
| Autor: | J. Wouter Jukema, Johann Wojta, Kjell Erik Julius Håkansson, Margreet R. de Vries, Reginald V.C.T. van der Kwast, Christoph Kaun, Eveline A. C. Goossens, Philipp J. Hohensinner, Stella Trompet, Jens Kastrup, Stefan Böhringer, Paul H.A. Quax, A. Yaël Nossent, Eva van Ingen, Saskia le Cessie, Rasmus S. Ripa |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Physiology Apolipoprotein E3 Disease 030204 cardiovascular system & hematology Mice 0302 clinical medicine Small nucleolar RNA Randomized Controlled Trials as Topic Aged 80 and over Genetics MEG3 Middle Aged Non-coding RNA Cardiovascular disease Up-Regulation Europe Phenotype Vascular tissue Cardiovascular Diseases Female Cardiology and Cardiovascular Medicine medicine.drug Mice Transgenic Single-nucleotide polymorphism Biology snoRNA Polymorphism Single Nucleotide STEMI 03 medical and health sciences 14q32 locus Physiology (medical) microRNA Human Umbilical Vein Endothelial Cells medicine Animals Humans RNA Small Nucleolar Genetic Predisposition to Disease DLK1-DIO3 Aged Chromosomes Human Pair 14 Fibrillarin urogenital system Mice Inbred C57BL Disease Models Animal 030104 developmental biology NIH 3T3 Cells Vessels Transcriptome Pravastatin Genome-Wide Association Study |
| Zdroj: | Cardiovascular Research, 115(10), 1519-1532 |
| ISSN: | 1519-1532 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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