TY - JOUR
T1 - Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis
AU - De Lillo, Antonella
AU - Pathak, Gita A.
AU - De Angelis, Flavio
AU - Di Girolamo, Marco
AU - Luigetti, Marco
AU - Sabatelli, Mario
AU - Perfetto, Federico
AU - Frusconi, Sabrina
AU - Manfellotto, Dario
AU - Fuciarelli, Maria
AU - Polimanti, Renato
N1 - Funding Information:
This study was supported by an Investigator-Initiated Research from Pfizer Inc. to the University of Rome Tor Vergata. Pfizer Inc. had no role in the study design, data analysis, and data interpretation of the present study .
Funding Information:
Drs. Fuciarelli and Polimanti received research grants from Pfizer Inc. to conduct epigenetic studies of hATTR. The other authors reported no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Amyloidosis
KW - Epigenetics
KW - hATTR
KW - Methylation
KW - Modifier gene
KW - Val30Met mutation
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U2 - 10.1186/s13148-020-00967-6
DO - 10.1186/s13148-020-00967-6
M3 - Article
C2 - 33203445
AN - SCOPUS:85096098063
VL - 12
JO - Clinical Epigenetics
JF - Clinical Epigenetics
SN - 1868-7075
IS - 1
M1 - 176
ER -