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

Marguerite R Irvin; Praful Aggarwal; Steven A Claas; Lisa de las Fuentes; Anh N Do; C Charles Gu; Andrea Matter; Benjamin S Olson; Amit Patki; Karen Schwander; Joshua D Smith; Vinodh Srinivasasainagendra; Hemant K Tiwari; Amy J Turner; Deborah A Nickerson; Dabeeru C Rao; Ulrich Broeckel; Donna K Arnett

doi:10.3389/fgene.2021.588452

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

Front Genet. 2021 Feb 19:12:588452. doi: 10.3389/fgene.2021.588452. eCollection 2021.

Authors

Marguerite R Irvin¹, Praful Aggarwal², Steven A Claas³, Lisa de las Fuentes⁴, Anh N Do¹, C Charles Gu⁵, Andrea Matter², Benjamin S Olson², Amit Patki⁶, Karen Schwander⁵, Joshua D Smith⁷, Vinodh Srinivasasainagendra⁶, Hemant K Tiwari⁶, Amy J Turner², Deborah A Nickerson⁷, Dabeeru C Rao⁵, Ulrich Broeckel², Donna K Arnett³

Affiliations

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.

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 height^2.7, 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.

Keywords: African-American; cardiomyocyte model; echocardiograph; exome sequencing; hypertension; left ventricular hypertrophy.

Abstract

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