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SMYD2 promoter DNA methylation is associated with abdominal aortic aneurysm (AAA) and SMYD2 expression in vascular smooth muscle cells

Published on Dec 1, 2018in Clinical Epigenetics5.496
· DOI :10.1186/s13148-018-0460-9
Bradley J. Toghill4
Estimated H-index: 4
(University of Leicester),
Athanasios Saratzis21
Estimated H-index: 21
(University of Leicester)
+ 2 AuthorsMatthew J. Bown36
Estimated H-index: 36
(University of Leicester)
Abstract
Abdominal aortic aneurysm (AAA) is a deadly cardiovascular disease characterised by the gradual, irreversible dilation of the abdominal aorta. AAA is a complex genetic disease but little is known about the role of epigenetics. Our objective was to determine if global DNA methylation and CpG-specific methylation at known AAA risk loci is associated with AAA, and the functional effects of methylation changes. We assessed global methylation in peripheral blood mononuclear cell DNA from 92 individuals with AAA and 93 controls using enzyme-linked immunosorbent assays, identifying hyper-methylation in those with large AAA and a positive linear association with AAA diameter (P < 0.0001, R2 = 0.3175). We then determined CpG methylation status of regulatory regions in genes located at AAA risk loci identified in genome-wide association studies, using bisulphite next-generation sequencing (NGS) in vascular smooth muscle cells (VSMCs) taken from aortic tissues of 44 individuals (24 AAAs and 20 controls). In IL6R, 2 CpGs were hyper-methylated (P = 0.0145); in ERG, 13 CpGs were hyper-methylated (P = 0.0005); in SERPINB9, 6 CpGs were hypo-methylated (P = 0.0037) and 1 CpG was hyper-methylated (P = 0.0098); and in SMYD2, 4 CpGs were hypo-methylated (P = 0.0012). RT-qPCR was performed for each differentially methylated gene on mRNA from the same VSMCs and compared with methylation. This analysis revealed downregulation of SMYD2 and SERPINB9 in AAA, and a direct linear relationship between SMYD2 promoter methylation and SMYD2 expression (P = 0.038). Furthermore, downregulation of SMYD2 at the site of aneurysm in the aortic wall was further corroborated in 6 of the same samples used for methylation and gene expression analysis with immunohistochemistry. This study is the first to assess DNA methylation in VSMCs from individuals with AAA using NGS, and provides further evidence there is an epigenetic basis to AAA. Our study shows that methylation status of the SMYD2 promoter may be linked with decreased SMYD2 expression in disease pathobiology. In support of our work, downregulated SMYD2 has previously been associated with adverse cardiovascular physiology and inflammation, which are both hallmarks of AAA. The identification of such adverse epigenetic modifications could potentially contribute towards the development of epigenetic treatment strategies in the future.
  • References (54)
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References54
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#1Bradley J. Toghill (University of Leicester)H-Index: 4
#2Athanasios Saratzis (University of Leicester)H-Index: 21
Last. Matthew J. Bown (University of Leicester)H-Index: 36
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Abstract Atherosclerosis and abdominal aortic aneurysms (AAAs) are multifactorial and polygenic diseases with known environmental and genetic risk factors that contribute toward disease development. Atherosclerosis represents an important independent risk factor for AAA, as people with AAA often have atherosclerosis. Studies have shown that comorbidity is usually between ~25% and 55%, but it is still not fully known whether this association is causal or a result of common shared risk profiles. M...
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#1Gregory T. JonesH-Index: 32
#2Gerard Tromp (Geisinger Medical Center)H-Index: 56
Last. Matthew J. Bown (University of Leicester)H-Index: 36
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Rationale:Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the h...
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#1Marc Jan Bonder (UG: University of Groningen)H-Index: 28
#2René Luijk (LEI: Leiden University)H-Index: 7
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Peter 't Hoen, Lude Franke, Bastiaan Heijmans and colleagues present a combined analysis of methylome and transcriptome data from a large collection of whole-blood samples to infer the downstream effects of disease-associated variants. They identify a large number of trait-associated SNPs influencing methylation of CpG sites in trans, providing insights into the downstream functional effects of many disease-associated variants.
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#1Bradley J. Toghill (University of Leicester)H-Index: 4
#2Athanasios Saratzis (University of Leicester)H-Index: 21
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Aortic aneurysmal disease may affect the thoracic and abdominal segments, but the pathophysiology and genetic causal background differ significantly. Abdominal aortic aneurysms (AAAs) are multifactorial and polygenic, whereas thoracic aortic aneurysms and dissections (TAAD) are typically familial and/or associated with certain syndromes. Various genomic loci have been linked to both diseases. Syndromic and nonsyndromic TAADs are the result of large-effect gene mutations in genes controlling extr...
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Objective First degree relatives of patients with abdominal aortic aneurysm (AAA) have an increased risk of developing AAA; however, despite intensive investigation, the specific genetic factors involved in the development of the disease are still largely unknown. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a gene...
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