PROJECT 1 ? Gene x Stress interactions' impacts on pathways to cardiometabolic disease PROJECT SUMMARY Our program, developed over 25 years of NHLBI support, has identified and continues to identify gene variants that interact with psychosocial stress to influence, via central nervous system and peripheral mechanisms, expression of behavioral and physiological endophenotypes in pathways to cardiometabolic disease and adverse clinical course. During the renewal period Project 1 will extend and substantially refine this work. Among the major challenges in studying gene by stress interactions are the need for a large number of individual observations in order to yield adequate statistical power and precision, and the relative absence of explicit measures of stress in prior studies. Project 1 addresses the first challenge by, in collaboration with the Biostatistics and Bioinformatics Core, harmonizing a number of large existing datasets, which will in turn be used to validate previous and newly discovered findings (Aim 1), and to embed those findings in the broader context of race (African Americans and Caucasians) (Aim 2) and potential mediating mechanisms that are thought to link variants to cardiometabolic disease. Project 1 overcomes the absence of explicit measures of stress by constructing a synthetic index of stress using bioinformatics techniques, which have proven successful in our preliminary work. We also will continue our discovery approach using high-throughput computational bioinformatics approaches, and gene x stress GWAS will be used in large publically accessible databases (e.g., MESA, FHS, CARDIA. Jackson Heart Study) to identify new gene variants associated with cardiometabolic endophenotypes (Aim 3). These newly discovered variants will be validated in new data derived from the harmonization. Project 1 also will pass previously and newly identified gene variants associated, both directly and via interaction with stress, with cardiometabolic endophenotypes to Project 2 (to test for effects on endophenotypes in pathways to type 2 diabetes), Project 3 (to test for effects on epigenetic, transcriptomic and metabolomics mechanism that mediate effects on endophenotypes and disease endpoints), and Project 4 (to test for effects on response of endophenotypes to behavioral and drug interventions). Successful completion of these aims will increase our understanding of gene x stress interactions that link stress to the development and course of cardiometabolic disease, knowledge that will be critical for the ultimate development of effective preventive and treatment interventions.

Public Health Relevance

PROJECT 1 - Genes, environmental stressors and the biobehavioral pathways to CVD PUBLIC HEALTH RELEVANCE Psychosocial stress is a key risk factor for many diseases. This Project analyzes large datasets from existing, well-characterized, relevant cohorts to identify both key stress-related and genetic characteristics that affect individual risks related to development, progression, and severity of cardiovascular disease, diabetes and other types of cardiometabolic disease. Of particular focus is identifying genetic variants whose interactions with stress exposures affect risk, so-called gene-by-stress interactions. The results of this work will enable refined identification of individuals at high risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL036587-25A1
Application #
9072716
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
25
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Ward-Caviness, Cavin K; Kraus, William E; Blach, Colette et al. (2018) Associations Between Residential Proximity to Traffic and Vascular Disease in a Cardiac Catheterization Cohort. Arterioscler Thromb Vasc Biol 38:275-282
Mirowsky, Jaime E; Devlin, Robert B; Diaz-Sanchez, David et al. (2017) A novel approach for measuring residential socioeconomic factors associated with cardiovascular and metabolic health. J Expo Sci Environ Epidemiol 27:281-289
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Jiang, Rong; Babyak, Michael A; Brummett, Beverly H et al. (2017) Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress. Psychoneuroendocrinology 79:13-19
Jiang, Rong; Babyak, Michael A; Brummett, Beverly H et al. (2017) Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort. Am Heart J 190:40-45
Haberstick, Brett C; Boardman, Jason D; Wagner, Brandon et al. (2016) Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health). PLoS One 11:e0148373
Ward-Caviness, Cavin K; Neas, Lucas M; Blach, Colette et al. (2016) Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease. PLoS One 11:e0152670
McGarrah, Robert W; Craig, Damian M; Haynes, Carol et al. (2016) High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort. Atherosclerosis 246:229-35
Ogle, Christin M; Rubin, David C; Siegler, Ilene C (2016) Accounting for Posttraumatic Stress Disorder Symptom Severity With Pre- and Posttrauma Measures: A Longitudinal Study of Older Adults. Clin Psychol Sci 4:272-286

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