Irvin Marguerite R, Aggarwal Praful, Claas Steven A, de las Fuentes Lisa, Do Anh N, Gu C Charles, Matter Andrea, Olson Benjamin S, Patki Amit, Schwander Karen, Smith Joshua D, Srinivasasainagendra Vinodh, Tiwari Hemant K, Turner Amy J, Nickerson Deborah A, Rao Dabeeru C, Broeckel Ulrich, Arnett Donna K
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Department of Pediatrics, Children's Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Genet. 2021 Feb 19;12:588452. doi: 10.3389/fgene.2021.588452. eCollection 2021.
: 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.
左心室（LV）结构和几何形状的指标代表了与左心室肥厚（LVH）相关的有用中间表型，LVH是心血管（CV）疾病（CVD）结局的预测指标。我们在高血压遗传流行病学网络（HyperGEN）的1364名非洲裔（AA）参与者中进行了一项全外显子组关联研究，研究对象为根据身高调整后的左心室质量（LVM）、左心室内径舒张末期内径（LVIDD）和相对壁厚（RWT）。进行了单变体和基于基因的序列核关联测试以检查常见和罕见编码变体是否导致AA人群超声心动图特征的变异。然后，我们使用数据驱动的程序对基因进行优先级排序，并选择基因使用人类诱导多能干细胞心肌细胞（hiPSC-CM）模型进行功能验证。基于统计显著性、变体功能注释、hiPSC-CM模型中的基因表达以及先前的生物学证据，对三个基因[肌球蛋白VIIA和Rab相互作用蛋白（）、运输蛋白颗粒复合体11（）和溶质载体家族27成员6（）]进行了优先级排序，随后在hiPSC-CM模型中对其进行敲低。敲低后肥厚基因标志物的表达谱分析表明肥厚表达谱降低。敲低显示心房利钠因子（）和脑利钠肽（）表达显著降低。心脏长链脂肪酸（FA）转运蛋白的敲低导致小窝蛋白3（）表达下调，这在动物模型中与肥厚表型有关。最后，敲低与钙处理缺陷有关。：这三个基因是生物学上合理的候选基因，为肥厚途径提供了新的见解。
