Abstract 233: Isoproterenol-induced Cardiac Hypertrophy And Failure In Mice: Gene Network Modeling

Abstract

Heart failure is highly heterogeneous and as a result, relatively few insights into the pathways and drivers of heart failure have been identified using system-wide methods such as genome-wide association studies (GWAS). We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) for high resolution GWAS and systems genetics in mice. Eight week old female mice from 93 unique inbred strains of the HMDP were given 20 μg/g/day of isoproterenol through an abdominally implanted Alzet micropump. Three weeks post-implantation, all mice were sacrificed, along with age-matched controls. The mice exhibited widely varying degrees of hypertrophy and heart functioning. A portion of the left ventricle was processed and arrayed on an Illumina Mouse Ref 8.0 platform. We used Maximal Information Component Analysis, a novel method of network construction which allows for non-linear relationships between genes as well as non-binary partitioning of genes into sub-networks to subdivide the expression data into a series of modules. In order to identify modules which may contribute to Isoproterenol-induced hypertrophy and failure, we examined the correlation of each module to clinically relevant cardiac traits traits such as organ weights and echocardiographic parameters. We identified several modules with strong correlations to multiple heart failure-related clinical traits, including one module of 41 genes which contained several genes of interest, including Lgals3, a diagnostic marker for heart failure. Utilizing eQTL hotspot analysis, we have identified a locus which is involved in the regulation of this module. A gene within this locus, Magi2, regulates the turnover of the β-adrenergic receptor and represents a likely candidate for the response to isoproterenol.