Genetic dissection of cardiac iron regulation using transcriptome network analysis and systems genetics in BXD mice

Cardiac iron homeostasis is essential for myocardial energy metabolism and contractile function, yet the genetic and molecular mechanisms governing iron levels within the heart remain poorly understood. We used a systems genetics approach to dissect the transcriptional regulation of cardiac iron homeostasis. Myocardial iron level varies substantially across BXD strains (40 - 112 μg/g) and is under heritable genetic control (H² = 0.38). Elevated cardiac iron is associated with reduced ventricular mass, increased ventricular ectopy, and prolonged atrioventricular conduction in the BXD population. Weighted gene co-expression network analysis of the BXD heart transcriptome identified a coexpression module that was significantly and negatively correlated with cardiac iron levels in both young and old BXD mice, and enriched for pathways related to metabolic regulation, cAMP signaling, circadian entrainment, and cardiovascular physiology. The module showed substantial overlap with a curated cardiac iron gene-set, and cross-species enrichment analysis confirmed its conservation in human cardiomyopathy differentially expressed genes (enrichment ratio = 1.49; FDR = 0.0342). Quantitative trait locus (QTL) mapping of the first principal component of the overlapping module iron genes (n = 38), corroborated by individual gene mapping, identified trans-eQTL hotspots on multiple chromosomes, implicating Fcho2, Gcc2, and Rmdn1 as candidate upstream regulators operating through sequential steps of intracellular iron trafficking. Together, these findings establish a systems-level map of cardiac iron gene regulation, identify candidate genetic regulators, and provide a molecular framework linking disruption of iron-related transcriptional networks to structural and electrical cardiac dysfunction with implications for iron-related heart diseases.