In the post-genomic era, high through put genome-wide scans and SNP association studies hold the promise of identifying new genes as significant risk factors for coronary artery disease (CAD) and myocardial infarction (MI). Such information raises a new challenge: how does an identified gene product influence disease? This was the challenge that emerged from GeneQuest I. This large-scale SNP case-control study in patients with familial, premature CAD/MI identified three gene that exhibited a significant association with MI. All three were members of the thrombospondin (TSP) gene family. The remarkable clustering of genes within a single family strongly implicates the TSP family in cardiovascular pathology, and this link is further bolstered by the replication of the TSP-2 and TSP-4 associations with MI in separate clinical studies and our own preliminary data showing that each of the three TSP SNP set displays distinct functions. This project will focus on TSP-4 and TSP-2. In TSP-4, the SNP leads to a A387 P substitution, occurs at high frequency (34% in the Caucasian population), and increases the risk of MI by almost 2-fold. In TSP-2, the SNP is a t3943g substitution in the 3'-untranslated region, occurs with high frequent (10%) and is protective (approximately 3-fold reduction in MI). The hypothesis to be tested is: the SNPs in TSP-4 and TSP-2 alter protein (TSP-4) or mRNA (TSP-2) structure, which affects the function and/or expression of the TSPs. Such alterations affect the responses of vascular cells, creating a pro- or anti-atherogenic environment in the vessel wall. To test this hypotheses, we will: 1) examine the influence of the TSP-4 and TSP-2 SNPs at a molecular and cellular level; 2) explore murine atherosclerosis and vascular injury models in which expression of the TSPs has been altered; 3) examine normal and atherosclerotic human vessels for SNP-dependent changes in mRNA and protein; 4) determine if the SNP variants induce different gene profiles consistent with their atherogenic effects; and 5) exploit the GeneBank of cardiology patients to establish additional associations of the TSPs with MI. The aggregate of these studies should provide a rigorous test of the hypothesis, extend our knowledge of the TSPs in cardiovascular disease; provide insights into their structure and function; and define general approaches to examine oathozenic mechanisms of other gene products that are linked to CAD and MI.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Special Emphasis Panel (ZHL1)
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Cleveland Clinic Lerner
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Xu, Huichun; Dorn 2nd, Gerald W; Shetty, Amol et al. (2018) A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans. J Pers Med 8:
Kim, Dae Joong; Christofidou, Elena D; Keene, Douglas R et al. (2015) Intermolecular interactions of thrombospondins drive their accumulation in extracellular matrix. Mol Biol Cell 26:2640-54
Lauer, Michael S (2014) Personal reflections on big science, small science, or the right mix. Circ Res 114:1080-2
Gao, Hanxiang; Li, Lin; Rao, Shaoqi et al. (2014) Genome-wide linkage scan identifies two novel genetic loci for coronary artery disease: in GeneQuest families. PLoS One 9:e113935
Sossey-Alaoui, Khalid (2013) Surfing the big WAVE: Insights into the role of WAVE3 as a driving force in cancer progression and metastasis. Semin Cell Dev Biol 24:287-97
Tang, W H Wilson; Shrestha, Kevin; Tong, Wilson et al. (2013) Nitric oxide bioavailability and adiponectin production in chronic systolic heart failure: relation to severity of cardiac dysfunction. Transl Res 162:26-33
Stenina-Adognravi, Olga (2013) Thrombospondins: old players, new games. Curr Opin Lipidol 24:401-9
Tang, W H Wilson; Shrestha, Kevin; Wang, Zeneng et al. (2013) Diminished global arginine bioavailability as a metabolic defect in chronic systolic heart failure. J Card Fail 19:87-93
Timur, A A; Murugesan, G; Zhang, L et al. (2012) P2RY1 and P2RY12 polymorphisms and on-aspirin platelet reactivity in patients with coronary artery disease. Int J Lab Hematol 34:473-83
Bhattacharyya, Sanghamitra; Sul, Kristina; Krukovets, Irene et al. (2012) Novel tissue-specific mechanism of regulation of angiogenesis and cancer growth in response to hyperglycemia. J Am Heart Assoc 1:e005967

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