MTSS1 in myocardial disease

University Of Pennsylvania, Philadelphia PA

Investigators

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Abstract

PROJECT SUMMARY Myocardial disorders lead to heart failure (HF) and impose an enormous public health burden. Changes in cardiac structure and function that accompany myocardial disease and HF are heritable traits. MTSS1 (metastasis suppressor 1) is an I-BAR protein that regulates cytoskeleton dynamics, cell motility, and adhesion. Our group identified genetic variants in a cardiac-specific enhancer upstream of MTSS1 that reduce human left ventricular (LV) MTSS1 expression, resulting in reduced LV size and reduced risk of dilated cardiomyopathy (DCM). These findings established MTSS1 as a genetic modifier of cardiac structure and function, and motivated the hypothesis MTSS1 reduction would protect against myocardial disease. In the first cycle of this award, we demonstrated that MTSS1 reduction partially rescues cardiac function in female but not male mice in vivo in a transgenic model of human DCM. To study effects in humans, we fine-mapped the MTSS1 locus with cardiac magnetic resonance imaging (CMR) traits in UK Biobank. Concordant with our mouse studies, associations between MTSS1 and CMR traits were evident almost exclusively in women, and MTSS1 alleles improved cardiac function in women—but not in men—who carried pathogenetic DCM variants. Our findings at the MTSS1 locus suggest a genetic basis for sex dimorphism in cardiac remodeling. Sex differences in cardiac traits and HF have been appreciated for decades. Remarkably, sex-specific effects have been largely ignored in cardiovascular genomics. Few genome wide association studies (GWAS) for cardiac traits and disease have been conducted separately in men and women; interactions between cardiac loci and sex or sex hormones are unexplored, and sex chromosomes themselves have been excluded from most GWAS. Our preliminary analyses indicate that MTSS1 is one of least 20 cardiac modifier loci that show sex dimorphism and may thus contribute to sex differences in myocardial disease. Our renewal application will elucidate sex-specific effects of modifier loci on cardiac structure, function, and failure using MTSS1 as an exemplar. Our approach will build on resources developed during the first award cycle, including consolidated access to global HF genomic data and experimental HF models already established in our laboratories. Aim I will determine genetic mechanisms through which MTSS1 and other modifier loci show sex-specific effects on cardiac traits. Aim II will test if sex-specific effects of MTSS1 and other modifiers will translate into sex differences in myocardial disease and clinical HF. Aim III will use experiments in HF models to prove, or refute, sex-specific mechanisms. If successful, our proposal will expand a paradigm revealed through MTSS1 into a broad understanding of genetic contributors to sex differences in myocardial disease. Doing so will advance cardiac biology, genetics, and precision medicine by identifying sex-specific risk factors and treatment targets for human heart failure.