TY - JOUR
T1 - Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP, TRAPPC11, and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population
AU - Irvin, Marguerite R.
AU - Aggarwal, Praful
AU - Claas, Steven A.
AU - de las Fuentes, Lisa
AU - Do, Anh N.
AU - Gu, C. Charles
AU - Matter, Andrea
AU - Olson, Benjamin S.
AU - Patki, Amit
AU - Schwander, Karen
AU - Smith, Joshua D.
AU - Srinivasasainagendra, Vinodh
AU - Tiwari, Hemant K.
AU - Turner, Amy J.
AU - Nickerson, Deborah A.
AU - Rao, Dabeeru C.
AU - Broeckel, Ulrich
AU - Arnett, Donna K.
N1 - Funding Information:
Funding. This study was funded by the US NIH National Heart, Lung and Blood Institute grants R01HL055673, U01HL107437, and R01HL125580.
Publisher Copyright:
© Copyright © 2021 Irvin, Aggarwal, Claas, de las Fuentes, Do, Gu, Matter, Olson, Patki, Schwander, Smith, Srinivasasainagendra, Tiwari, Turner, Nickerson, Rao, Broeckel and Arnett.
PY - 2021/2/19
Y1 - 2021/2/19
N2 - 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.
AB - 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.
KW - African-American
KW - cardiomyocyte model
KW - echocardiograph
KW - exome sequencing
KW - hypertension
KW - left ventricular hypertrophy
UR - http://www.scopus.com/inward/record.url?scp=85102295941&partnerID=8YFLogxK
U2 - 10.3389/fgene.2021.588452
DO - 10.3389/fgene.2021.588452
M3 - Article
C2 - 33679876
AN - SCOPUS:85102295941
SN - 1664-8021
VL - 12
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 588452
ER -