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.
