Functional GWAS for LVH using iPS-derived Cardiomyocytes: The HyperGEN ciPS Stud

描述(由申请人提供)： 这笔赠款的总体重点是跟进一项最大的多种族全基因组关联研究之一的左心室重量(LVM)和左心室肥厚(LVH)的结果。我们建议使用诱导多能干细胞(IPS)技术来研究和理解LVM增加导致LVH作为心血管疾病常见和主要危险因素的遗传基础下的复杂分子机制和途径。这项赠款申请为将流行病学和遗传学研究扩展到功能水平奠定了基础，该研究是NHLBI‘高血压遗传流行病学网络’-ECHO(HyperGEN-ECHO)研究的一部分，该研究的重点是识别左室肥厚的基因。HyperGen队列是最大的基于家庭的队列之一，拥有高加索人和非裔美国人的超声心动图数据。我们在每个种族中进行了一项基于家庭的GWA研究，并确定了与LVM和其他相关表型相关的SNPs和基因。与以流行病学为基础的GWA研究一样，这些发现缺乏功能注释，已识别的SNP之间的相互作用仍有待阐明。人类诱导多能干细胞(IPSC)技术的出现为这一问题提供了实验解决方案。人IPSC来源的心肌细胞表现出与其原代心肌细胞高度相似的特性，因此可以用作所需功能分析的模型系统。我们建议进一步改进高效生成IPSCs和心肌细胞的方案(第一阶段)；开发和扩大技术和基础设施，为非裔美国人和高加索人(250名捐赠者)中信息最丰富的100个家庭生产IPSCs和心肌细胞(第二阶段)；衍生IPSCs和心肌细胞，并通过分析不同条件下表达的变化来研究与LVH发展相关的分子变化。利用基于家族的eQTL分析，我们将研究DNA变异对这些与GWAS(第三阶段)中发现的SNPs相关的分子变化的影响。新的分析方法将致力于确定新的疾病途径，作为未来自动治疗干预的目标。 (摘要结束)

DESCRIPTION (provided by applicant): The overall focus for this grant is to follow-up findings from one of the largest multi-ethnic genome-wide association studies for Left Ventricular Mass (LVM) and Left Ventricular Hypertrophy (LVH). We propose to use induced pluripotent stem cell (IPS) technology to investigate and understand the complex molecular mechanisms and pathways underlying the genetic basis of an increase in LVM leading to LVH as a common and major risk factor for cardiovascular disease. This grant application lays the foundation for extending the epidemiological and genetic research conducted as part of the NHLBI 'Hypertension Genetic Epidemiology Network' - Echo (HyperGEN-ECHO) study, which focuses on the identification of genes for LVH, to a functional level. The HyperGen cohort is one of the largest family-based cohorts with echocardiographic data for both Caucasians and African-Americans. We have performed a family-based GWA study in each ethnicity and identified SNPs and genes related to LVM and other related phenotypes. As common to epidemiologically-based GWA studies, these findings lack functional annotation and the interplay between identified SNPs remains to be elucidated. The advent of human induced pluripotent stem cell (iPSC) technology provides a experimental solution to this problem. Human iPSC-derived cardiomyocytes exhibit properties highly similar to their primary counterparts, thus can be used as a model system for the required functional analysis. We propose to further improve protocols for the efficient generation of iPSCs and cardiomyocytes (Phase I); develop and scale-up the technology and infrastructure to produce iPSCs and cardiomyocytes for 100 of the most informative families in both African-Americans and Caucasians (250 donors) (Phase II); derive iPSCs and cardiomyocytes, and study the molecular changes associated with the development of LVH by analyzing expression changes under various conditions. Using family-based eQTL analysis, we will study the impact of DNA variation on these molecular changes associated with SNPs identified in GWAS (Phase III). Novel analysis methods will aim to identify new disease pathways as future targets for therautic interventions. (End of Abstract)