Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP , TRAPPC11 , and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population
: 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. We conducted an exome-wide association study of LV mass (LVM) adjusted to height , LV internal diastolic dime...
Gespeichert in:
Veröffentlicht in: | Frontiers in genetics 2021-02, Vol.12, p.588452 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | : 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.
We conducted an exome-wide association study of LV mass (LVM) adjusted to height
, 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 (
), trafficking protein particle complex 11 (
), and solute carrier family 27 member 6 (
)] 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.
knockdowns showed a significant decrease in atrial natriuretic factor (
) and brain natriuretic peptide (
) expression. Knockdowns of the heart long chain fatty acid (FA) transporter
resulted in downregulated caveolin 3 (
) expression, which has been linked to hypertrophic phenotypes in animal models. Finally,
knockdown was linked to deficient calcium handling.
: The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways. |
---|---|
ISSN: | 1664-8021 1664-8021 |
DOI: | 10.3389/fgene.2021.588452 |