The overarching long range goal of this program project is to carry out translational research leading to the identification of genetic variants that act to increase the expression of endophenotypes that lead over time to the development of CVD and Type 2 diabetes (T2D), a major CVD risk factor. The central organizing theme of our research toward this goal over the next five years posits that genes and environmental exposures to various acute and chronic stressors across the life cycle influence - via both main and interactive effects -brain neurotransmitter systems in ways that affect the expression of health behaviors, psychological traits and states and neuroendocrine/autonomic functions in ways that alter metabolic, hemostatic, inflammatory and cardiovascular functions that are the proximal contributors to the development of T2D and/or CVD and/or precipitation of acute clinical events. Project 1 will use three existing samples with extensive data on these CVD and T2D endophenotypes to identify promising gene variants - using both candidate genes and GWAS-derived SNPs associated with T2D and CVD ~ that can be evaluated in Projects 2 and 3 for association with the same or similar predisease endophenotypes and CVD and/or T2D prevalence/incidence in two large cohorts. Project 2 will attempt to replicate the gene associations with the same or similar T2D and/or CVD endophenotypes found in Project 1 and test those variants for association with CVD and T2D in a large healthy nationally representative cohort, the Add Health sample (N=15,608). Project 3 will test these genetic variants for association with CVD &T2D and clinical events in a large cohort (N =8,000 -10,000) of Duke CAD patients who have undergone coronary angiography.

Public Health Relevance

The knowledge gained can be used to guide the development of the new field of prospective medicine, in which individuals at high risk of developing CVD and/or T2D can be identified earlier in the pathogenic process - before tissue damage has occurred - and targeted for preventive interventions to slow or prevent the development of disease and/or improve prognosis once disease is present.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-PPG-Z (F4))
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Czajkowski, Susan
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Duke University
Schools of Medicine
United States
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Singh, Abanish; Babyak, Michael A; Nolan, Daniel K et al. (2015) Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene. Eur J Hum Genet 23:854-62
Brummett, Beverly H; Babyak, Michael A; Kuhn, Cynthia M et al. (2014) A functional polymorphism in the HTR2C gene associated with stress responses: a validation study. Biol Psychol 103:317-21
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Jiang, Rong; Brummett, Beverly H; Hauser, Elizabeth R et al. (2013) Chronic family stress moderates the association between a TOMM40 variant and triglyceride levels in two independent Caucasian samples. Biol Psychol 93:184-9
Ogle, Christin M; Rubin, David C; Siegler, Ilene C (2013) The impact of the developmental timing of trauma exposure on PTSD symptoms and psychosocial functioning among older adults. Dev Psychol 49:2191-200
Brummett, Beverly H; Babyak, Michael A; Singh, Abanish et al. (2013) Socioeconomic indices as independent correlates of C-reactive protein in the National Longitudinal Study of Adolescent Health. Psychosom Med 75:882-93
Nolan, Daniel; Kraus, William E; Hauser, Elizabeth et al. (2013) Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family. PLoS One 8:e71779

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