Impact of Epigenetics on the Development of Transthyretin Amyloid Cardiomyopathy: A Systematic Literature Review

Author(s): Nuno Marques, Joana Apolónio, Isabel Palmeirim, Pedro Castelo Branco, Olga Azevedo

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by deposition of variant or wild-type transthyretin in the heart. However, the impact of epigenetic modulation on the development of ATTR-CM is yet to be unveiled, warranting the need for a systematic review of the literature.

Methods: A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on PubMed and Embase databases on December 20th, 2024. Studies were selected based on the following predefined eligibility criteria: English-language studies or case series, including adult patients diagnosed with ATTR-CM, assessing the impact of epigenetics on the development of the disease. Relevant data were extracted to a predefined template. Quality assessment was based on the checklist by Newcastle – Ottawa Quality Assessment Scale for Case- Control Studies.

Results: From 170 records, 3 publications were selected, describing 3 casecontrol studies. Two studies evaluated DNA methylation and one assessed microRNA profiles. Both DNA methylation studies evaluated the hereditary form of ATTR amyloidosis (ATTRv). One study found an hypomethylation at cg09097335 in ATTRv carriers compared to controls, while the other study identified five hypomethylated sites in Val142Ile individuals with heart disease: cg06641417 (FAM129B); cg26033908 (SKI); cg14890866 (WDR27); cg15522719 (GLS)cg18546846 (RP11-550A5.2; intergenic). The study on microRNA profiling identified an upregulation of miR-339-3p in wild-type ATTR amyloidosis patients compared to controls. The limitations of these three studies do not allow to draw definitive conclusions.

Conclusions: This systematic review of the literature highlights the need for larger and well-balanced studies to evaluate the impact of epigenetics on the development of ATTR-CM.