Global and regional DNA methylation patterns in heart failure: a case-control analysis

Heart failure (HF) is a syndrome of heterogeneous aetiology and multiple exposomal causes. The role of DNA methylation (DNAm) changes in symptomatic HF and its phenotypes is unclear. This work addresses global and regional DNAm patterns and epigenetic ageing in HF.

Patients with HF were included from the MyoVasc Study, an investigator-initiated prospective cohort study. Individuals without HF were included from a population-based Gutenberg Health Study. DNAm was measured using the Illumina Infinium MethylationEPIC assay. Epigenetic ageing was calculated using GrimAge and Hannum methylation clocks.

Global DNAm patterns were analysed across 767,735 CpG sites in a dataset of N = 2155 individuals. HF was associated with an increase of epigenetic age by on average 19.0 [11.0; 29.0] years and with a global decrease in methylation across all phenotypes (Odds ratio [OR]: 1.33 [95% CI: 1.17-1.51], p < 0.0001). Epigenetic clocks strongly predicted incident worsening of HF and mortality. Methylation differences varied across chromosomes and were most pronounced in shore (OR: 1.41 [95% CI: 1.25-1.61], p < 0.0001) region. CpG island methylation had a weaker association with HF status (p = 0.0122), but strongly interacted with methylation in adjacent regions.

This work highlights accelerated ageing, global and regional methylation patterns as key features associated with the presence, severity, and consequences of HF. HF-related methylation exhibited diverse patterns across chromosomes, the genome, and gene regions. CpG islands lacked strong discriminatory capacity, but their potential regulatory role is a novel finding.

SHARP, BMBF, DZHK, CTVB, DIASyM, Stiftung Rheinland-Pfalz für Innovation, ReALity, curATime.