Epigenetic Profiling Identifies Novel Genes for Ascending Aortic Aneurysm Formation with Bicuspid Aortic Valves

  • Asad A Shah Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
  • Simon G. Gregory Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Deidre Krupp Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Sheng Feng Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Allison Dorogi Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Carol Haynes Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Elizabeth Grass Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
  • Shu S. Lin Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
  • Elizabeth R. Hauser Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
  • William E. Kraus Division of Cardiology, Duke University Medical Center, Durham, NC
  • Svati H. Shah Division of Cardiology, Duke University Medical Center, Durham, NC
  • G. Chad Hughes Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC

Abstract

Background:  Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized.  We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.

Methods:  Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves.  Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays.  Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test.  

Results:  Twenty-seven probes in 9 genes showed significant differential methylation and expression (P<5.5x10-4).  The top gene was protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10-5) in bicuspid patients, as compared to tricuspid patients.  Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range:  -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissections

Conclusions:  Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms.  The top gene was PTPN22, which is involved in T-cell receptor signaling and associated with various immune disorders.  These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

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Published
2015-08-30
Section
Articles