Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study

Area of Science:

• Epigenetics
• Cardiovascular Research
• Molecular Biology

Background:

• Atrial fibrillation (AF) is the most common cardiac arrhythmia, with poorly understood molecular mechanisms of arrhythmogenesis.
• Epigenetic modifications, such as DNA methylation, regulate gene expression and influence biological processes.
• The role of DNA methylation in AF susceptibility remains largely unexplored.

Purpose of the Study:

• To investigate the association between genome-wide DNA methylation patterns and atrial fibrillation.
• To identify potential DNA methylation signatures linked to the development and presence of AF.
• To explore the relationship between known AF-related genetic variants and DNA methylation.

Main Methods:

• Genome-wide DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip.
• Blood DNA samples from 2,639 participants in the Framingham Heart Study Offspring Cohort were analyzed.
• Statistical analyses, including correction for multiple testing (FDR < 0.05), were used to identify significant CpG sites associated with prevalent and incident AF.

Main Results:

• Seven CpG sites were significantly associated with AF (two with prevalent AF, five with incident AF) after multiple testing correction.
• Fourteen previously reported AF-related single nucleotide polymorphisms (SNPs) showed associations with at least one CpG site.
• A strong association was observed between rs6490029 (CUX2 locus) and cg10833066 (P = 9.5 × 10⁻²⁷⁹).

Conclusions:

• This study identified seven novel DNA methylation signatures associated with atrial fibrillation.
• The findings suggest that DNA methylation plays a significant role in the molecular mechanisms underlying AF arrhythmogenesis.
• Epigenetic mechanisms, specifically DNA methylation, represent a potential avenue for understanding AF susceptibility and progression.