Although psychosocial stress has been hypothesized to play a role in the etiology of cardiovascular disease, empirical verifications of the effects of stress and the biological mechanisms through which stress operates remain rare. A major limitation has been the absence of population studies with direct biologic measures of stress (such as measures of levels of stress hormones), so that their link to social antecedents and to biological precursors of cardiovascular disease can be studied. It has also become increasingly apparent that social conditions and stressors must interact with genetic makeup, and that some of these exposures may modify gene expression through changes in DNA methylation but few population studies have comprehensively investigated the gene-environment interactions and epigenetic changes related to psychosocial factors. A major goal of this project is to better understand the ways in which socially patterned stress interacts with genetics and biology to influence cardiovascular-related outcomes. Using data from the Multiethnic Study of Atherosclerosis, a large, multiethnic population sample, we propose to investigate long-term associations of the stress response (as characterized by multiple measures of stress hormones) with social/psychosocial antecedents and cardiovascular-related outcomes, as well as modifications of the stress response by variations in selected candidate genes, and links between psychosocial factors and epigenetic changes.
The Specific Aims of the project are: (1) To examine associations of repeat measures of stress hormones with social and psychosocial factors and with biological precursors of cardiovascular disease including inflammation/hemostasis and measures of insulin resistance and adiposity;(2) To examine interactions between cortisol levels and polymorphisms of the glucocorticoid receptor gene with respect to cardiovascular-related outcomes;(3) To examine the extent to which polymorphisms of biologically relevant genes modify the response to a psychological stress challenge;and (4) To examine epigenetic changes (DNA methylation) of the glucocorticoid receptor gene as well as genomic DNA methylation and their association with (a) lifecourse social exposures;(b) cortisol and hemodynamic responses to a stress challenge;and (c) biological parameters previously linked to stress exposures. Our study will enhance our understanding not only of the epidemiologic links between stress and cardiovascular disease but also of the biologic mechanisms (involving genetic polymorphisms and changes to gene expression) through which these effects may be mediated. By illustrating how the study of genetic variability, biological markers, and social conditions can be integrated to enhance our understanding of the causes of ill health our project has the potential for contributing to major paradigmatic change in health research.

Public Health Relevance

It has been argued that stress may be important to the development of cardiovascular disease, but few population studies have comprehensively investigated the way in which stress operates. This study will investigate the links between stress and biological factors important to cardiovascular disease, including the interactions between stress and genes. This approach is necessary to better understand the importance of stress and to develop preventative interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101161-03
Application #
8241157
Study Section
Special Emphasis Panel (ZRG1-PSE-A (02))
Program Officer
Srinivas, Pothur R
Project Start
2010-06-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$1,109,024
Indirect Cost
$144,466
Name
University of Michigan Ann Arbor
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Rudolph, Kara E; Sánchez, Brisa N; Stuart, Elizabeth A et al. (2016) Job Strain and the Cortisol Diurnal Cycle in MESA: Accounting for Between- and Within-Day Variability. Am J Epidemiol 183:497-506
Ware, Erin B; Smith, Jennifer A; Mukherjee, Bhramar et al. (2016) Applying Novel Methods for Assessing Individual- and Neighborhood-Level Social and Psychosocial Environment Interactions with Genetic Factors in the Prediction of Depressive Symptoms in the Multi-Ethnic Study of Atherosclerosis. Behav Genet 46:89-99
Fujishiro, Kaori; Diez Roux, Ana V; Landsbergis, Paul et al. (2015) Occupational characteristics and the progression of carotid artery intima-media thickness and plaque over 9 years: the Multi-Ethnic Study of Atherosclerosis (MESA). Occup Environ Med 72:690-8
Ware, Erin B; Mukherjee, Bhramar; Sun, Yan V et al. (2015) Comparative genome-wide association studies of a depressive symptom phenotype in a repeated measures setting by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis. BMC Genet 16:118
Joseph, Joshua J; Wang, Xu; Spanakis, Elias et al. (2015) Diurnal salivary cortisol, glycemia and insulin resistance: The multi-ethnic study of atherosclerosis. Psychoneuroendocrinology 62:327-35
He, Zihuai; Zhang, Min; Lee, Seunggeun et al. (2015) Set-based tests for genetic association in longitudinal studies. Biometrics 71:606-15
Needham, Belinda L; Smith, Jennifer A; Zhao, Wei et al. (2015) Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis. Epigenetics 10:958-69
Merkin, Sharon Stein; Karlamangla, Arun; Elashoff, David et al. (2015) Change in cardiometabolic score and incidence of cardiovascular disease: the multi-ethnic study of atherosclerosis. Ann Epidemiol 25:912-7.e1
He, Zihuai; Payne, Erin K; Mukherjee, Bhramar et al. (2015) Association between Stress Response Genes and Features of Diurnal Cortisol Curves in the Multi-Ethnic Study of Atherosclerosis: A New Multi-Phenotype Approach for Gene-Based Association Tests. PLoS One 10:e0126637

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