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Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP , TRAPPC11 , and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population

Authors
  • Irvin, Marguerite R.1
  • Aggarwal, Praful2
  • Claas, Steven A.3
  • de las Fuentes, Lisa4
  • Do, Anh N.1
  • Gu, C. Charles5
  • Matter, Andrea2
  • Olson, Benjamin S.2
  • Patki, Amit6
  • Schwander, Karen5
  • Smith, Joshua D.7
  • Srinivasasainagendra, Vinodh6
  • Tiwari, Hemant K.6
  • Turner, Amy J.2
  • Nickerson, Deborah A.7
  • Rao, Dabeeru C.5
  • Broeckel, Ulrich2
  • Arnett, Donna K.3
  • 1 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL , (United States)
  • 2 Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI , (United States)
  • 3 College of Public Health, University of Kentucky, Lexington, KY , (United States)
  • 4 Cardiovascular Division, Department of Medicine and Division of Biostatistics, Washington University, St. Louis, MO , (United States)
  • 5 Division of Biostatistics, Washington University, St. Louis, MO , (United States)
  • 6 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL , (United States)
  • 7 Department of Genome Sciences, University of Washington, Seattle, WA , (United States)
Type
Published Article
Journal
Frontiers in Genetics
Publisher
Frontiers Media SA
Publication Date
Feb 19, 2021
Volume
12
Identifiers
DOI: 10.3389/fgene.2021.588452
PMID: 33679876
PMCID: PMC7933688
Source
PubMed Central
Keywords
License
Unknown

Abstract

Background : Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. Methods and Results: We conducted an exome-wide association study of LV mass (LVM) adjusted to height2.7, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein ( MYRIP ), trafficking protein particle complex 11 ( TRAPPC11 ), and solute carrier family 27 member 6 ( SLC27A6 )] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. MYRIP knockdowns showed a significant decrease in atrial natriuretic factor ( NPPA ) and brain natriuretic peptide ( NPPB ) expression. Knockdowns of the heart long chain fatty acid (FA) transporter SLC27A6 resulted in downregulated caveolin 3 ( CAV3 ) expression, which has been linked to hypertrophic phenotypes in animal models. Finally, TRAPPC11 knockdown was linked to deficient calcium handling. Conclusions : The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.

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