Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA

Author:

Shabani Mahsima1,Wang Min2ORCID,Jenkins Gregory D.3,Rotter Jerome I.4ORCID,Rich Stephen S.5ORCID,Batzler Anthony3,Taylor Kent D.4ORCID,Mychaleckyj Josyf C.5,Liu Duan2ORCID,Lima Joao A.C.16ORCID,Pereira Naveen L.27ORCID

Affiliation:

1. Division of Cardiology, Department of Medicine (M.S., J.A.C.L.), Johns Hopkins University School of Medicine, Baltimore, MD.

2. Department of Molecular Pharmacology and Experimental Therapeutics (M.W., D.L., N.L.P.), Mayo Clinic, Rochester, MN.

3. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (G.D.J., A.B.), Mayo Clinic, Rochester, MN.

4. The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (J.I.R., K.D.T.).

5. Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R., J.C.M.).

6. Department of Radiology and Radiological Science (J.A.C.L.), Johns Hopkins University School of Medicine, Baltimore, MD.

7. Department of Cardiovascular Medicine (N.L.P.), Mayo Clinic, Rochester, MN.

Abstract

BACKGROUND: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. METHODS: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. RESULTS: The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume ( P= 0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume ( P= 0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 ( P= 7.3×10 -22 ). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1–mediated α-smooth muscle actin and collagen expression. CONCLUSIONS: Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging–based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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