Abstract 14489: The Pathogenesis of Marfan Syndrome Involves Epigenetic Regulation of Signalling

IntroductionMarfan syndrome (MFS), a connective tissue disorder resulting from a defect in the fibrillin-1 gene, is the most common form of heritable thoracic aortic aneurysm. Greater insight into the underlying pathophysiology of aneurysm formation through epigenetic analysis aims to determine the association and epigenetic patterns of individual genes and signal networks to aid treatment and risk stratification of patients diagnosed with MFS.HypothesisDifferences in the epigenetic pattern of DNA methylation between MFS patients and controls will reflect pathological signalling in MFS.MethodsCirculating white cell DNA from MFS patients (n= 17), and age and sex matched controls (n=18) was examined using an epigenome-wide association study (Infinium Human Methylation 450 BeadChip Kit).ResultsWe interrogated 485,000 methylation sites per sample at single-nucleotide resolution, identifying 154 sites (0.03% of dataset) and 1568 sites (0.32% of dataset) that were very significantly increased or decreased (fold change >1.5), respectively, in MFS compared to control. We identified 294 signal networks in the KEGG database that are differentially methylated in MFS. Specifically, we demonstrated substantial epigenetic up-regulation of the TGF-β pathway through a significant decrease in methylation at CpG loci of a majority of the identified members of the TGF-β pathway (65%). Importantly, in the majority of genes, methylation changes localised to the promoter region of that gene, thus further implicating these genes in the underlying pathogenesis of MFS. Finally, we showed similar up-regulation of activity in TAA-associated pathways including MAPK, PI3K-Akt, vascular smooth muscle contraction and the calcium signalling pathway as well as the novel base excision repair pathway.ConclusionsThese data support the hypothesis that aberrant signalling due to altered DNA methylation patterns, particularly in the TGF-β pathway, contributes to the pathogenesis of MFS. Thus, the use of demethylase or kinase inhibitors may be a therapeutic option to ameliorate the course of aneurysm formation, two therapeutic options that are finding increasing clinical utility, for example in cancer.