The overarching objective of this Project is to identify genetic variants and environmental factors that act, whether interactively or Independently (main effects), to influence the expression of a wide range of psychosocial, behavioral and biological characteristics [CVD and Type 2 Diabetes (T2D) endophenotypes] that increase the risk of developing CVD and T2D among healthy persons as well as increase the risk of adverse clinical events in persons in whom CVD is already manifest. To achieve this objective we shall use use three samples - PPG-1 (N=165), Caregiver (170 caregivers of a relative with Alzheimer's Disease, 170 controls) and PPG-2 (644 from 400 families);with a total N of 1000+/- - in which we have extensive data re a broad range of T2D and CVD endophenotypes to identify promising genetic variants (using both candidate genes and GWAS-derived SNPs) that are associated with these predisease endophenotypes. A major thrust of our work on this Project will be to increase our confidence in the reality of these geneendophenotype associations by replicating them, both within the three samples used by Project 1 and in the large healthy and clinical CAD samples being studied in Projects 2 and 3.
A third aim will be to work closely with Projects 2 and 3 to complete the tranlational process, by showing that the genetic variants found associated in Project 1 with T2D and CVD endophenotypes are also associated in those Projects'samples with both the prevalence and incidence of CVD and T2D and clinical course.

Public Health Relevance

The knowledge gained in Project 1 and its collaboration with Projects 2 and 3 will consitute important progress toward the long range goal identifying persons at risk of developing CVD or T2D earlier in the pathogenic process, so that they, and the CVD and/or T2D endophenotype(s) accounting for their increased risk, can be targeted for interventions, to prevent the development of disease or improve prognosis.

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)
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Duke University
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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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