Epigenetic profiling of Italian patients identified methylation sites associated with hereditary Transthyretin amyloidosis

Hereditary Transthyretin (TTR) Amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers, We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (beta =-0.60, p=6.26x10-8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology:0050435, q=0.007), amyloid fiber formation (Reactome HSA-977225, q=0.008), and Alzheimers disease (KEGG hsa05010, q=2.2x10-4). Additionally, TTR and BACE2 share APP (Amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (beta=-2.18, p=3.34x10-11). Cg13139646 showed co-methylation with cg19203115 (r2=0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (beta=-0.56, p=8.6x10-4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.