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

ABSTRACT: 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 (standardized regression coefficient?=?-0.60, p?=?6.26?×?10-8). 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 Alzheimer's disease (KEGG hsa05010, q?=?2.2?×?10-4). 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 (standardized regression coefficient?=?-2.18, p?=?3.34?×?10-11). Cg13139646 showed co-methylation with cg19203115 (Pearson's r2?=?0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient?=?-0.56, p?=?8.6?×?10-4). 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.

SUBMITTER: De Lillo A 

PROVIDER: S-EPMC7672937 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature