Abstract P382: Transcriptomic Analysis Of Human Left Atrial Tissue Reveals Mitochondrial Gene Co-expression

Abstract

Atrial fibrillation (AF) risk is heritable. High rate electrical activity in AF requires increased energy. Atrial mitochondrial structure and function are altered in AF patients in an effort to generate adequate ATP through oxidative phosphorylation. Genomic studies have identified putative AF risk genes, but the association of AF risk genes with expression of mitochondrial genes is unclear. We tested the hypothesis that putative AF risk genes are co-expressed with mitochondrial genes that play a role in atrial energy production. RNA-seq was performed on left atrial appendage (LAA) tissues obtained from 251 cardiac surgery patients. RNA coexpression profiles were evaluated for 222 putative AF risk genes. Genes encoding proteins that localize to the mitochondria were identified using MitoCarta 2.0. Changes in metabolic pathways were detected using Ingenuity Pathway Analysis (IPA). Our analysis identified 128 AF risk genes that coexpressed with at least one mitochondrial gene. The highest level of mitochondrial gene coexpression was evident with PCCB, in which 30% (253 of 848) of coexpressed genes were mitochondrial. CASQ2 (24%, 104 of 431) and ASAH1 (20%, 37 of 182) also showed high levels of mitochondrial gene coexpression. The IPA Oxidative Phosphorylation Pathway was significantly altered (p<0.05) for 26 AF risk genes, with CASQ2 (9.42E-79), MYH6 (4.73E-78), YWHAE (4.96E-75), and TTN (4.30E-71) the most strongly associated (Table). Additionally, 12 AF risk genes coexpressed with genes encoded by mitochondrial DNA (mtDNA) (Table). ASAH1, CASQ2, MYH6, NACA, NUCKS1, PLN, TTN, and YWHAE coexpressed with all 13 mtDNA encoded components of the electron transport chain. Many AF risk genes show significant coexpression with mitochondrial genes. We propose that genetic risk scores based on these AF risk genes may identify a subset of AF patients that would benefit from AF therapies that enhance metabolic activity.