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Twin pairs discordant for incident coronary artery disease reveal epigenetic and transcriptomic differences by gene
Asmus Cosmos Skovgaard1, Mikael Thinggaard2, Jacob vB Hjelmborg2
1The Danish Twin Registry and the Research Unit for Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. acskovgaard@health.sdu.dk.
Insights
Coronary artery disease (CAD) involves unique DNA methylation patterns that alter gene expression, particularly affecting immune-inflammation and muscle biology pathways. These findings highlight novel biomarkers for CAD and the importance of multi-omics research.
Area of Science:
- Genetics and Epigenetics
- Cardiovascular Research
- Molecular Biology
Background:
- Cardiovascular diseases (CVDs), especially coronary artery disease (CAD), are leading global causes of mortality.
- Existing epigenomic and transcriptomic studies of CAD lack the power of discordant twin designs to control for genetic factors.
- No prior research has linked DNA methylation sites to gene expression levels specifically within the context of CAD.
Purpose of the Study:
- To identify novel biomarkers for coronary artery disease (CAD).
- To investigate the relationship between DNA methylation and gene expression in discordant twin pairs.
- To explore multi-omics patterns associated with CAD development.
Main Methods:
- Utilized genome-wide DNA methylation (CpG) and gene expression (probe) data from 44 Danish twin pairs discordant for incident CAD.
- Identified differentially methylated CpGs and gene expression probes within twin pairs using Cox regression analysis.
- Performed gene set enrichment and interaction network analyses on genes with concordant or discordant methylation and expression patterns.
Main Results:
- CAD co-twins exhibited distinct DNA methylation patterns, leading to up-regulated gene expression compared to their non-CAD co-twins.
- Observed specific patterns of promoter demethylation and gene body methylation associated with CAD.
- Identified immune-inflammation pathways as predominantly up-regulated and muscle system biology pathways as down-regulated in CAD co-twins.
Conclusions:
- Uncovered a specific DNA methylation-gene expression pattern linked to coronary artery disease (CAD).
- Suggests novel multi-omics biomarkers for CAD, emphasizing immune-inflammation and muscle biology.
- Highlights the rarity and importance of multi-omics studies in understanding complex diseases like CAD.
Abstract:
Cardiovascular diseases are the leading causes of mortality globally, of which coronary artery disease (CAD) is the most frequent. Several epigenomics and transcriptomics studies of CAD have been conducted, however, only a few studies have utilized the statically powerful discordant twin pair design, which reduces the confounding introduced by genetics. Finally, no study has investigated the link between the DNA methylation position and gene expression levels. The present study aims at filling this knowledge gap, to present novel biomarkers of CAD. We investigated 44 Danish twin pairs that were discordant for incident CAD, for whom, both genome-wide DNA methylation (CpG) and gene expression (probe) data were available. We identified CpGs and probes, which were more different within the twin pairs than expected by change, and investigated these by Cox regression analysis. CpGs and probes belonging to the same gene were divided into groups based on their directions of effect, and these genes were investigated by gene set enrichment and interaction network analyses. Overall, we found that CAD co-twins showed DNA methylation patterns leading to up-regulated gene expression; especially with demethylation of promoters and methylation of gene bodies, compared to their non-CAD co-twin. Generally, we found that the largest biological group of up-regulated pathways related to immune-inflammation processes, whereas down-regulated pathways related to muscle system biology, among others. Hence, the present study uncovers a specific pattern between DNA methylation position and gene expression levels relating to CAD, pointing to a need for additional studies. However, such multi-omics designs are surprisingly rare.
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