Abstract 9035: Epigenetic Modifications are Associated with Ascending Thoracic Aneurysm Formation in Patients with Bicuspid Aortic Valve

Objective: Bicuspid aortic valve (BAV) disease predisposes to early and more frequent ascending thoracic aortic aneurysm formation, but the mechanisms underlying this aortopathy remain incompletely characterized. The objective of this study was to identify genes predisposing to ascending aneurysm formation in patients with BAV aortopathy using a multipronged molecular approach. Methods: Ascending aortic aneurysm tissue samples were collected at the time of ascending aortic replacement in subjects with bicuspid (N=16) and trileaflet (N=16) aortic valves. All patients in the trileaflet valve group had degenerative aneurysms and those with connective tissue disorders were excluded. Using the aortic tissue samples, genome-wide DNA methylation status was determined using Illumina 450K methylation chips. Gene expression was determined using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet groups using Wilcoxon Rank Sum tests. Results: Twenty-six genes were differentially methylated between the bicuspid and trileaflet groups, and six of these genes also had significantly different gene expression between groups. Protein tyrosine phosphatase, non-receptor type 22 ( PTPN22 ) was strongly hypermethylated (beta: bicuspid 0.68 vs. trileaflet 0.55, P=4x10 -5 ) and had a resultant highly significant decrease in gene expression (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10 -5 ). Conclusions: In patients with ascending thoracic aortic aneurysms, there exist differential DNA methylation and gene expression signatures between those with BAV aortopathy versus acquired degenerative aneurysms and trileaflet aortic valves. The strongest finding was for PTPN22 , a gene involved in T-cell receptor signaling and associated with various autoimmune disorders. These differences may highlight novel mechanisms of aneurysm development in the BAV population, potentially serving as biomarkers and/or pharmacologic targets.