Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidos
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RESEARCH
Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis Antonella De Lillo1, Gita A. Pathak2,3, Flavio De Angelis1,2,3, Marco Di Girolamo4, Marco Luigetti5,6, Mario Sabatelli6,7, Federico Perfetto8, Sabrina Frusconi9, Dario Manfellotto4, Maria Fuciarelli1 and Renato Polimanti2,3*
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. Keywords: hATTR, Amyloidosis, Val30Met mutation, Epigenetics, Methylation, Modifier gene Background Hereditary transthyretin amyloidosis (hATTR; OMIM#105210) is a life-threatening disorder caused by transthyretin (TTR) protein misfolding. This causes amyloid fibril deposition in several tissues (e.g., peripheral nerves, heart, and gastrointestinal tract) [1, 2]. hATTR is *Correspondence: [email protected] 2 Department of Psychiatry, Yale University School of Medicine, VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT, USA Full list of author information is available at the end of the article
characterized by extreme clinical heterogeneity including age of onset, penetrance, and clinical display [3–5]. To date, more than 130 amyloidogenic mutations have been identified in the coding regions of the TTR gene, which are the cause of hATTR [6]. The prevalence of hATTR is estimated to be approximately 1/100,000 [7]. hATTR endemic areas have bee
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