Abstract 15407: Humanity in a Dish: Investigating a Common Genetic Basis for Human Metabolic Disease With Induced Pluripotent Stem Cells
Introduction: The NHLBI Framingham Heart Study (FHS) is a prospective community-based study focused on the epidemiology of myocardial infarction (MI) and other forms of cardiovascular disease. One limitation of this study is a lack of primary human tissues for in vitro observation of cellular phenotypes contributing to disease pathophysiology.
Methods: To address this limitation of the FHS and other community-based cohort studies, we collected peripheral blood cells from FHS participants and reprogrammed a subset ascertained at a genetic variant rs12740374 to induced pluripotent stem cells (iPSCs). We differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the documented effect of rs12740374 on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures.
Hypothesis: Increased SORT1 expression affects dysregulation of intracellular lipid accumulation and gene expression in hepatocytes carrying the minor 1p13 genotype.
Results: Using metabolomics and transcriptomics, we observed a strong association between rs12740374 and SORT1 expression, lipid accumulation, and genotype-driven gene expression changes in differentiated hepatocytes. Numerous trans-expression quantitative trait loci were identified, and lipid accumulation was generally decreased in hepatocytes carrying the minor allele at rs12740374.
Conclusions: iPSC cohorts enable accurate modeling of the effect of common non-coding genetic variants on cardiometabolic phenotypes. The minor allele of rs12740374 has a metabolic effect on hepatocytes, which may be mediated directly by sortilin function or indirectly by modulation of gene expression in trans. The success of this methodology in describing new biological phenomena heralds the next generation of population genetics studies: performed in the dish, and driven by iPSC technology.
Author Disclosures: C.R. Warren: None. J.F. O’Sullivan: None. M. Friesen: None. C.E. Becker: None. X. Zhang: None. P. Liu: None. Y. Wakabayashi: None. J.E. Morningstar: None. X. Shi: None. J. Choi: None. F. Xia: None. D.T. Peters: None. M.H. Florido: None. A.M. Tsankov: None. E. Duberow: None. L. Comisar: None. J. Shay: None. X. Jiang: None. A. Meissner: None. K. Musunuru: None. S. Kathiresan: None. L. Daheron: None. J. Zhu: None. R.E. Gerszten: None. R. Deo: None. R.S. Vasan: None. C.J. O’Donnell: None. C.A. Cowan: None.
- © 2016 by American Heart Association, Inc.