Using NGS-methylation profiling to understand the molecular pathogenesis of young MI patients who have subsequent cardiac events

Abstract

Globally, ischaemic heart disease is a major contributor to premature morbidity and mortality. A significant number of young Myocardial Infarction (MI) patients (aged <55 y) have subsequent cardiac events within a year of their index event. This study used Next Generation Sequencing (NGS) methylation to understand the pathogenesis in this subset of young MI patients, comparing them to a cohort of patients without recurrent events. Cases and controls were matched for age, gender, ethnicity, and comorbidities. Differential methylation analyses were performed on Reduced Representation Bisulphite Sequencing (RRBS) data. Across the group and within case-control pairs' variation were analysed. Pairwise comparisons across each matched case-control pair resulted in a list of genes that were consistently significantly differentially methylated between all 16 matched pairs. This gene list was input into pathway analysis databases. Of particular relevance to cardiac pathology the following pathways were identified as over-represented in the patients with recurrent events; cell adhesion, transcription regulation and cardiac electrical conduction, specifically relating to calcium channel activity. This study looked at methylation differences between two populations of young MI patients. There were significantly different methylation profiles between the two groups studied; key pathways were identified as specifically affected in the patients with recurrent cardiac events. Matched pairwise comparisons and detailed interpretations of DNA methylation data may help to elucidate complex pathogeneses within and between clinical subtypes. Further analysis will determine whether these epigenomic differences can be useful as predictive biomarkers of clinical progression.

A review on regulation of DNA methylation during post-myocardial infarction

“…Currently, medications such as aspirin, warfarin, tissue plasminogen activator, and interventional therapy, such as percutaneous coronary intervention (PCI), are the mainstay of treatment for AMI ( Lu et al, 2015 ; Doenst et al, 2019 ; Sabatine and Braunwald, 2021 ). However, unpredictable complications such as bleeding, ischemia/reperfusion injury, and coronary restenosis may occur, highlighting the need for safer and more innovative therapeutic strategies to optimize clinical outcomes ( McCarthy et al, 2018 ; Doenst et al, 2019 ; Mackman et al, 2020 ; Zhang et al, 2022 ).Several studies have observed significant individual methylation differences in patients with MI ( Ek et al, 2016 ; Rask-Andersen et al, 2016 ; Thunders et al, 2019 ; Han et al, 2022 ; Luo et al, 2022 ; Ren et al, 2022 ). Further exploration of the regulatory mechanisms of DNA methylation and its potential impact on metabolism and vascular physiology after MI may help reduce the incidence of post-MI complications ( Ward-Caviness et al, 2018 ).…”

“…Research has demonstrated alterations in the degree of methylation of certain genes in individuals with myocardial infarction ( Ek et al, 2016 ; Rask-Andersen et al, 2016 ; Ward-Caviness et al, 2018 ; Thunders et al, 2019 ), which are associated with cardiac function, cardiogenesis, and recovery after ischemic injury. To understand the early dynamic changes of gene expression after MI, RNA-seq and MeDIP-seq were used on heart tissues from AMI mice at different time points ( Han et al, 2022 ; Luo et al, 2022 ), and the results showed that DNA methylation plays an important role in the pathophysiological progression after MI.…”

Protocol for generating high-quality genome-scale DNA methylation sequencing data from human cancer biospecimens

“…We have used the protocol described here for several human cancers 1 , 2 , 3 , 4 , 5 and have also successfully used it for DNA methylation analysis of other human diseases, 6 , 7 , 8 normal human cells, 9 , 10 mice, 11 zebrafish, 12 , 13 , 14 , 15 and mangrove rivulus. 16 …”