Much of the risk for atherosclerotic coronary heart disease (CHD) is genetic in nature, and genome wide association based studies have recently been employed to identify CHD-related variation. One of the novel loci identified through the large-scale Coronary ARtery DIsease Genome wide Replication and Meta- analysis (CARDIoGRAM) study of whole genome data for 22,233 cases and 64,762 controls is located on chromosome 6 at q23.2, within the locus encoding the basic helix-loop-helix (bHLH) transcription factor TCF21. Six of the most highly associated SNPs in the CARDIoGRAM study are correlated eQTL variants within and upstream of the gene that form a disease-associated haplotype. Some of these variants are predicted to disrupt transcription factor or miRNA binding sites that likely regulate TCF21 expression. The bHLH transcription factors are well known to regulate cell fate decisions that are critical for embryonic developmental and disease-related pathways. TCF21 was first cloned in this and two other laboratories and shown to mark progenitor cells that give rise to the coronary circulation. Targeted deletion of Tcf21 has been associated with disrupted vascular smooth muscle cell (SMC) development, and in vitro studies have implicated TCF21 as an important regulator of transcription and cell fate decisions in SMC. The simple LD structure in this locus, and the known identity of the causal CHD-associated gene, suggest molecular, cellular, and animal model experimental approaches to identifying upstream and downstream signaling pathways to elucidate the mechanisms by which variation in this locus contributes to CHD risk. Studies proposed here will identify the mechanisms by which variation at 6q23.2 alters TCF21 expression and function, and the vascular cell pathways that are dysregulated in SMC in this regard to promote CHD. Experiments in Specific Aim 1 will investigate whether disease-associated or correlated variation regulates TCF21 expression. These studies will characterize DNA-binding transcription factors and mRNA-binding miRNA and regulatory proteins, providing insights into upstream signaling pathways that mediate the risk associated with this region.
In Specific Aim 2, the downstream TCF21 genetic program will be characterized by identifying the in vivo binding sequences and related genes that are regulated by this transcription factor in vascular SMC, employing combined ChIP-Seq and gene expression approaches.
Specific Aim 3 will employ targeted deletion of Tcf21 in murine vascular atherosclerosis and remodeling models to provide mechanistic insights into the cellular and molecular aspects of disease risk, and Specific Aim 4 will further investigate these molecular pathways with in vitro cellular models. Together, these studies are expected to provide a comprehensive picture of the mechanisms by which variation in the TCF21 locus alters basic SMC function and predisposes to vascular disease.
) Significant expense and effort by groups of scientists around the world has led to identification of regions of the human genome that are associated with the genetic risk for various forms of cardiovascular disease. Additional research is required to understand the specific genes involved, and how they work to contribute to the disease process. Such information will allow the development of better therapeutics for these diseases.
|Liu, Boxiang; Pjanic, Milos; Wang, Ting et al. (2018) Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci. Am J Hum Genet 103:377-388|
|Carcamo-Orive, Ivan; Huang, Ngan F; Quertermous, Thomas et al. (2017) Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. Arterioscler Thromb Vasc Biol 37:2038-2042|
|Assimes, Themistocles L; Lee, I-T; Juang, Jyh-Ming et al. (2016) Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium. PLoS One 11:e0138014|
|Knowles, Joshua W; Xie, Weijia; Zhang, Zhongyang et al. (2016) Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J Clin Invest 126:403|
|Winkler, Thomas W (see original citation for additional authors) (2016) Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet 12:e1006166|
|Priest, James R; Osoegawa, Kazutoyo; Mohammed, Nebil et al. (2016) De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet 12:e1005963|
|Quertermous, Thomas; Ingelsson, Erik (2016) Coronary Artery Disease and Its Risk Factors: Leveraging Shared Genetics to Discover Novel Biology. Circ Res 118:14-6|
|Pjanic, Milos; Miller, Clint L; Wirka, Robert et al. (2016) Genetics and Genomics of Coronary Artery Disease. Curr Cardiol Rep 18:102|
|Kojima, Yoko; Volkmer, Jens-Peter; McKenna, Kelly et al. (2016) CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536:86-90|
|Priest, James Rush; Gawad, Charles; Kahlig, Kristopher M et al. (2016) Early somatic mosaicism is a rare cause of long-QT syndrome. Proc Natl Acad Sci U S A 113:11555-11560|
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