Po-02-146 multi-omics analysis reveals the metabolic and polygenic basis of brugada syndrome

Brugada syndrome (BrS) is an inherited disorder that can lead to sudden cardiac death. Candidate genes primarily include those encoding the sodium channel, whereas other genetic variants affecting other channels, signaling, scaffold, sarcomere, and mitochondrial proteins are controversial, leaving the genetic architecture of BrS largely unknown. The aim of this work was to improve the diagnosis and prognosis of BrS, further understanding of its molecular basis by performing the first study that integrates genetics, transcriptomics, proteomics, metabolomics, and lipidomics in patients with and without BrS. Transcriptomics, proteomics, metabolomics, lipidomics, and whole-genome sequencing analyzes were performed on PBMCs and plasma samples of 293 patients with BrS and 295 control patients. These datasets were integrated to provide a comprehensive view of the molecular pathways and genetic factors underlying BrS. WGS showed that polygenic factors contribute to BrS and that there is genetic overlap with arrhythmogenic, cardiovascular, and noncardiac pathologies. This complex genetic background includes pathogenic mutations in SCN5A and in other genes such as CACNB2, MUC4, CHIT1, MME, PFKFB3, ACSF3, ACACB, SLC27A6, PLCG2, and MT-CYB. Many of them regulate metabolic functions related to lipid metabolism and energy production. Transcriptomics and proteomics analyses of PBMCs independently confirmed dysregulation of signaling pathways, indicative of chronic oxidative and metabolic abnormalities. This was reflected in changes in metabolomics and lipidomics, including downregulation of the TCA cycle, decreased ATP production, and evidence of a shift from oxidative phosphorylation to glycolysis. Integration of multi-omics and analysis of patients' peripheral blood cells revealed dysregulation of ubiquitous metabolic pathways, revealing that BrS is not limited to the heart. This challenges the traditional classification of BrS as a cardiac channelopathy and suggests a possible role of mutations in metabolic genes and pathways in the disease pathophysiology.