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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  r  2  = 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.

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