Differential Methylation in the GSTT1 Regulatory Region in Sudden Unexplained Death and Sudden Unexpected Death in Epilepsy.

Steffan Noe Christiansen,Kristine Boisen Olsen,Stine Bøttcher Jacobsen,Jeppe Dyrberg Andersen,Jytte Banner,Linea Christine Trudsø,Jacob Tfelt-Hansen,Niels Morling,Marie-Louise Kampmann

doi:10.3390/ijms22062790

Abstract

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.

Highlights

IntroductionThe majority of sudden cardiac deaths (SCDs) in the young are suspected to result from undiagnosed structural cardiovascular disorders that can be identified at post-mortem investigations [3,4]
The study included ten males and four females diagnosed with sudden unexpected death in epilepsy (SUDEP) and six males and three females diagnosed with sudden unexplained death (SUD) (Table 1)
The analysis revealed that PC2 tended to overall difference between SUDEP

Summary

Introduction

The majority of sudden cardiac deaths (SCDs) in the young are suspected to result from undiagnosed structural cardiovascular disorders that can be identified at post-mortem investigations [3,4]. In cases of a structurally normal heart, routine autopsies often fail to identify a disease as the cause of death. These sudden unexplained deaths (SUDs) are presumed to be caused by undiagnosed cardiac arrhythmias and are, in the case of a negative histological and toxicological investigation, termed sudden arrhythmic death syndrome [5,6]. Diseases most commonly associated with SUD are inherited cardiac channelopathies such as long QT syndrome (LQTS), Brugada Syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) [7,8]. The role of epigenetic patterns in SUD remains largely undetermined

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