- Project Title: DNA methylation & adversity: pathways from exposures to health inequities
- Project Number: 5R01MD014304-04
- Opportunity Number: PAR-16-355
- Contact PI/Project Leader: KRIEGER, NANCY; RELTON, CAROLINE
- Awardee Organization: HARVARD SCHOOL OF PUBLIC HEALTH
- Project Start Date: 01-September 2019
- Project End Date: 31-March-2024
- For more information please visit: https://reporter.nih.gov/project-details/10363700
Our study will test novel hypotheses about how one type of epigenetic modification, DNA methylation (DNAm), varies with exposure to racial discrimination, economic hardship, and air pollution, and how these kinds of epigenetic changes may contribute to racial/ethnic and economic disparities in cardiometabolic disease risk and accelerated aging (defined as epigenetic age > chronological age). To strengthen the credibility of our findings, we test our hypotheses in two independent population-based studies, using: (1) the My Body, My Story (MBMS) study (R01 AG027122), which contains rich exposure and cardiometabolic health outcome data based on a random sample of 1005 US-born non-Hispanic black (n = 504) and non-Hispanic white (n = 501) adults, aged 35 to 64 years, recruited from four community health centers in Boston, MA (2008-2010), and for which we will newly analyze DNA methylation based on the participants’ stored blood spots; and (2) newly available analogous data from a subset of Wave 5 (2010-2012) participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (N = 1264, age 55-94; 582 non-Hispanic white, 270 non-Hispanic black, 404 Hispanic, from Baltimore, MD, Forsyth County, NC, NYC, NY, and St. Paul, MN). The proposed study accordingly will address the objective of PAR-16-355 to “expand approaches for understanding epigenetic mechanisms by which social factors lead to biological changes that affect health disparities.”
Aim 1: Conduct novel analyses to identify variation in DNA methylation (DNAm) associated with: (1) Aim 1.1: exposure to racial discrimination, economic hardship, and air pollution; and (2) Aim 1.2: measured cardiometabolic outcomes (blood pressure, fasting insulin, Type 2 diabetes, Framingham Cardiovascular Disease 10-year risk score, metabolic syndrome); plus (3) Aim 1.3: For DNAm-health outcome associations observed in Aim 1.2, use MR-Base (a database and analytical platform for Mendelian randomization being developed by the MRC Integrative Epidemiology Unit at the University of Bristol) to strengthen causal inference about the direction of the associations (e.g., methylation causes vs. is due to disease); discovery analyses: My Body My Story study data; replication analyses: Multi-Ethnic Study of Atherosclerosis study data.
Aim 2: Assess the relationships between both the Aim 1 study exposures and health outcomes with accelerated aging (epigenetic age > chronological age), as identified by three newly identified DNAm “clocks” (Horvath, Hannum, and DNAm PhenoAge); discovery: MBMS; replication: MESA. Epigenetic “clocks” measure DNAm age and are comprised of specified sets of DNAm sites. These clocks “tick” in all cells and their descendants across the lifecourse and provide a “molecular estimator” of an organism’s biological age. To ensure robust test of our hypotheses, we will use 3 different validated “clocks”: the Horvath and Hannum “clocks,” both created in 2013, and the 2nd generation DNAm PhenoAge “clock,” developed in 2018.
Aim 3: Analyze if the methylation sites and “clocks” associated with both the study exposures and health outcomes mediate these exposure-outcomes associations, thereby contributing to health inequities.