Abstract 12987: A Combined Analysis of the Transcriptional Response of iPS-cell Derived Human Cardiomyocytes and GWAS for Left Ventricular Hypertrophy Reveals Common Biology in Both African American and Caucasians
Left ventricular hypertrophy (LVH) is a significant and independent risk factor for cardiovascular disease. Previously we have conducted a family-based GWAS in the HyperGEN cohort (Caucasians, Cau, 1304 individuals; African Americans, AA, 1256 individuals) and identified a number of SNPs associated with LVH. However, understanding how individually identified, and often functionally unannotated, SNPs contribute to the disease mechanism has remained a major challenge. Moreover, with little overlap in AA and Cau association signals it is unknown if common pathways underlie the LVH phenotype in these groups. Human cardiomyocytes derived from induced pluripotent stem-cells (iPSC) provide a new model to study cardiovascular biology. We established a novel iPSC derived human cardiomyocyte model of hypertrophy, using transcriptional profiling to identify candidate functional modules in the LVH GWAS results to test the hypothesis that common biological mechanisms are perturbed in both Cau and AA. Global expression profiling was performed to find differentially expressed genes in human iPSC cardiomyocytes stimulated for 3 days with each of three hypertrophy inducing agents ( angiotensin II (10-5 M), endothelin 1 (10-6 M) and isoproterenol (10-5 M). We applied gene set enrichment analysis using these functionally derived sets to the GWAS results of both AA and Cau cohorts. All three stimulation sets provided significantly enriched gene groups in both ethnicities (FDR <= 0.004 for each agent in both ethnicities, 5000 permutations). Of the genes differentially expressed with isoproterenol, 64 enrich in Cau and 58 in AA with 46 overlapping (p=0.002). This includes previously linked genes such as CDH13, CSMD1 and LIPG in addition to novel candidate genes including SORCS1, MN1 and NR4A3, not previously implicated in cardiomyocyte biology. The significant overlap between the two ethnic groups provides evidence of common functional gene groups contributing to the development of LVH. In conclusion, combining iPSC cardiomyocytes transcriptional profiling with GWAS data reveals novel candidate mechanisms for LVH in common between Cau and AA. The established methods also provide the basis for future direct functional characterization in human cardiomyocytes.
- Stem cells
- Cardiac hypertrophy
- Genome-wide association studies (GWAS)
- Gene expression
- Cardiovascular disease
- © 2011 by American Heart Association, Inc.