Sex-Specific Effect of MTSS1 Downregulation on Dilated Cardiomyopathy

Abstract

AbstractMTSS1 (metastasis suppressor 1) is an I-BAR protein that regulates cytoskeleton dynamics through interactions with actin, Rac, and actin-associated proteins. In a prior study, we identified genetic variants in a cardiac-specific enhancer upstream ofMTSS1that reduce human left ventricular (LV) MTSS1 expression and associate with protection against dilated cardiomyopathy (DCM). We sought to probe these effects further using population genomics andin vivomurine models. We crossedMtss1-/-mice with a transgenic (Tg) murine model of human DCM caused by the D230N pathogenic mutation inTpm1(tropomyosin 1). In females,Tg/Mtss1+/-mice had significantly increased LV ejection fraction and reduced LV volumes relative to theirTg/Mtss1+/+counterparts, signifying partial rescue of DCM due toMtss1haploinsufficiency. No differences were observed in males. To study effects in humans, we fine-mapped theMTSS1locus with 82 cardiac magnetic resonance (CMR) traits in 22,381 UK Biobank participants.MTSS1enhancer variants showed interaction with biological sex in their associations with several CMR traits. After stratification by biological sex, associations with CMR traits and colocalization withMTSS1expression in the Genotype-Tissue Expression (GTEx) Project were observed principally in women and were substantially weaker in men. These findings suggest sex dimorphism in the effects of MTSS1-lowering alleles, and parallel the increased LV ejection fraction and reduced LV volumes observed femaleTg/Mtss1+/-mice. Together, our findings at theMTSS1locus suggest a genetic basis for sex dimorphism in cardiac remodeling and motivate sex-specific study of common variants associated with cardiac traits and disease.