Abstract 232: A Genome-wide Association of Murine Echocardiographic Measures Implicates Muscle A-type Lamin-interacting Protein (MLIP) in Isoproterenol-induced Interventricular Septal Hypertrophy
Genome-wide association studies of heart failure in humans have yielded limited results, largely due to highly heterogeneous environmental and genetic backgrounds. The Hybrid Mouse Diversity Panel consists of inbred strains that are either fully sequenced or densely genotyped and as a whole displays significant natural variations. We assessed the hypothesis that precise environmental control, a well-defined genetic background, and a careful and uniform phenotyping scheme enable high-resolution mapping of cardiac remodeling in an isoproterenol-induced heart failure mouse model. Eight to ten-week old females from 105 inbred mouse strains (average N per strain = 6.7) were divided into control (average N per strain = 2.5) and treated (average N per strain =4.1) cohorts. Treated mice received 20 μg/g/day of isoproterenol through an abdominally implanted Alzet micropump for 3 weeks. All mice underwent echocardiography at baseline and at weekly time points. Phenotypic data were analyzed using the Efficient Mixed-Model Association (EMMA) algorithm to correct for population substructure. Our study showed that chronic isoproterenol administration resulted in marked inter-strain variations in echocardiographic measurements across the mouse panel. EMMA analysis of the data revealed many significant association peaks across echocardiographic measures. The most significant association signal is in the change of diastolic interventricular septal wall thickness between baseline and 1 week after isoproterenol treatment, a marker of early isoproterenol-induced left ventricular hypertrophy. The peak SNP rs13480288 (p-value of 4.0580e-09) and its surrounding SNPs (within correlation r2 > 0.8) span across 3 genes. Of these, Mlip alone harbors a missence variant and a splice-site variant across our panel. Mlip, also known as muscle A-type lamin-interacting protein, is expressed abundantly in the heart and interacts directly with A-type lamins in the nuclear envelope. Mutations in A-type lamins have been shown to cause both hypertrophic and dilated cardiomyopathy. In conclusion, our study results provide strong evidence that genetic variations in Mlip contribute to differential responses in interverntricular septal hypertrophy to isoproterenol.
- © 2013 by American Heart Association, Inc.