Coronary heart disease (CHD) is a growing medical problem in minority groups in this country and is predicted to become epidemic in regions of Sub-Saharan Africa, countries of the Mideast and India. New treatment options are needed that will expand beyond known risk factors to target primary disease processes in the blood vessel wall. In this regard, recent large-scale genome wide association studies (GWAS) have identified 46 genome wide significant CHD loci and a further 104 independent variants strongly associated with a 5% false discovery rate. A majority of the causal genes in these loci function independently of risk factors. It is postulated that a number of the CHD associated genes regulate basic cellular processes in the vascular smooth muscle cell (SMC), a critical mediator of atherosclerosis, and that study of the signaling pathways that are modulated in this cell type by causal regulatory variation will provide critical new insights for targeting the initiation and progression of disease. The primary goals of work proposed here are to identify CHD associated genes that exhibit allele specific expression (ASE) in SMC, map the causal variation responsible for this ASE, and characterize the transcriptional signaling pathways that are modulated by these regulatory variants. The work proposed here will build on recent studies identifying causal variation at 6q23.2 and elucidating the growth factor and developmental signaling pathways that regulate the basic helix-loop-helix transcription factor TCF21, a known critical regulator of embryonic vascular SMC development. A newly developed microfluidics multiplex PCR sequencing approach will be employed for evaluating allele-specific expression in vascular SMC, and these ASE data used to map the causal regulatory variation in CHD associated loci. Transcription factor binding sites that colocalize with causal regulatory variatio, and allele-specific transcription factor binding and transactivation will be characterized. Correlation will be made to chromatin architecture in these regions of the genome, and association with epigenetic signaling investigated. In vivo significance of these data will be provided by mouse transgenic reporter gene studies that map temporal and cell-specific expression directed by the causal transcription factor binding sites in the context of vascular development, SMC response to injury and contribution to atherosclerotic disease. Taken together, these data will provide critical information regarding the upstream signaling pathways and specific mechanisms that mediate the CHD risk in GWAS loci for this phenotype.

Public Health Relevance

Half of the risk for coronary heart disease and heart attacks is due to the genes inherited from one's parents. Understanding of the mechanisms by which specific genes affect risk could lead to the development of new approaches to treating this disease. In experiments described here we propose to dissect the specific molecular pathways by which coronary heart disease associated genes contribute to the risk for this deadly and debilitating condition. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHL1-CSR-H (S1))
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Hasan, Ahmed a K
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Assimes, Themistocles L; Quertermous, Thomas (2014) Study of exonic variation identifies incremental information regarding lipid-related and coronary heart disease genes. Circ Res 115:478-80
Miller, Clint L; Assimes, Themistocles L; Montgomery, Stephen B et al. (2014) Dissecting the causal genetic mechanisms of coronary heart disease. Curr Atheroscler Rep 16:406