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.

Case Report: Transthyretin Glu54Leu—a rare mutation with predominant cardiac phenotype

“…Broad intra and interfamilial variations in terms of age of onset and severity have been observed in ATTRv amyloidosis, caused by diverse mutations. Therefore, we can speculate that genetic modifiers and epigenetic factors are causing such variability (21,22). Future research should be conducted to reach more definitive conclusions.…”

The genome of the black-footed cat: Revealing a rich natural history and urgent conservation priorities for small felids

“…4 F ). In addition, TTR and a second gene B4GALT6 , which are also strongly linked to amyloidosis in mice and human ( 21 , 22 ), are located in the ROH region of the BFC. Moreover, a missense deleterious mutation (alanine to glycine) on the 37th amino acid site of another gene related to amyloidosis ( BACE1 ) was found in the BFC.…”

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

“…Variability in phenotype and penetrance of ATTRv amyloidosis can conceivably be explained by epigenetic modifications especially when we consider monozygotic twins that carry the same variant yet display different clinical presentations [59][60][61][62] In an epigenome-wide association study (EWAS) on 48 carriers (38 symptomatic and 10 asymptomatic) of TTR variants Val30Met, Phe64Leu, Ala120Ser, Ile68Leu, and Val122Ile and 32 controls, it was found that a CpG site in the Beta-secretase 2 (BACE2) gene was significantly hypomethylated in variant carriers [123]. BACE2 is known for cleaving APP in the brain, but is also present in peripheral tissues in inflammatory responses leading to the hypothesis that there might be a link between BACE2 and TTR-induced inflammation.…”