Arteriosclerosis of the cardiac, cerebral, renal and peripheral arteries are often caused by high blood pressure and can lead to target organ damage and clinical sequelae such as heart attack, stroke, dementia and chronic kidney disease. While arteriosclerosis affects all human populations, it imposes greater health risks in underrepresented population such as African Americans. Indeed, greater progression of coronary atherosclerosis was observed in African-American patients, suggesting a more aggressive form of disease that requires intensification of secondary prevention strategies in African Americans. Here, we propose to investigate the epigenetic mechanism underlying the risk of arteriosclerosis in the underrepresented population of African Americans. We will do so by identifying DNA methylation sites that are causally associated with arteriosclerosis related clinical phenotypes in African Americans (N=1,848) from a predominately hypertensive cohort -- the Genetic Epidemiology Network of Arteriopathy (GENOA). We have already collected the whole genome sequencing data through the Trans-Omics for Precision Medicine initiative (TOPMed) on these individuals. We have collected genome wide methylation data in peripheral blood leukocytes based on the Infinium Human Methylation EPIC BeadChip on these individuals. We have also collected phenotypic measurements for arteriosclerosis that include coronary artery calcification, leukoaraiosis, microvascular arteriopathy of the kidneys, as well as peripheral arterial disease on these individuals.
In this proposal, we aim to pair the DNA sequencing data, methylation data as well as the arteriosclerosis related phenotypic data in the GENOA cohort to investigate the causal epigenetic mechanism underlying arteriosclerosis. Specifically, we propose to (1) adapt the recently developed transcriptome wide association studies (TWAS) statistical method that has been widely used in transcriptomic analysis setting to methylation analysis settings. While the adaptation is straightforward, we will explore the connection of existing TWAS approach to the Mendelian randomization framework that are commonly used for causal inference in association studies to facilitate results interpretation. (2) With existing or adapted tools, we will perform an in-depth methylome wide association study, by treating cis-SNPs of each methylation site as instrumental variables, to identify methylation sites that are causally associated with each of the arteriosclerosis related phenotypes. In the analysis, we will carefully control for batch effects and various confounding factors. (3) When necessary, for the identified top candidate methylation sites, we will perform an experimental validation by adding methylation to the targeted regions and examining the consequence of these targeted methylation in cultured human cell lines. Targeted region methylation will be performed by using existing Type I CRISPR-Cas system based methylation tool to add methylation precisely and robustly on a specified region of the genome. The success of these proposed interdisciplinary aims will allow us to identify and validate DNA methylation sites that causally associated with arteriosclerosis, potentially providing novel epigenetic targets and facilitating translational research on arteriosclerosis. The proposal has the potential to produce synergistic efforts across multiple research disciplines to benefit the translational research of cardiovascular disease and improve patient outcomes.
Please Note This Project Is Now Closed.
The Michigan Institute for Clinical & Health Research (MICHR) seeks innovative translational research projects that will ultimately have significant potential to improve patient and community health outcomes. The goal of this funding is to support interdisciplinary research teams in generating sufficient preliminary data to pursue future extramural funding and publication opportunities. We welcome research proposed at any stage of translation, including:
- preclinical research that aims to connect the basic science of disease with human medicine
- clinical research to better understand a disease in humans
- clinical implementation, involving the adoption of interventions demonstrated useful in the research environment into routine clinical care, and
- the study of health outcomes at the population level to determine the effects of diseases and efforts to prevent, diagnose and treat them
MICHR will fund up to five Classic Cubes ($60K) and 13 Mini Cubes ($15K).
No unit or faculty contribution is required.
Project Submission Process
Interested faculty members please provide the following information to be considered for funding:
Click the Comments tab above, and post a project idea in the Mcubed website. Please do not exceed two paragraphs in length. Provide basic details about the proposed research.
Comment should also include:
- Three cube collaborators - faculty names and units. The team must include 3 faculty from at least 2 units, and 1 faculty member on each team must be from Medicine.
- Grant amount requested ($15K or $60K)
- Studies proposing cell or animal models should provide reasoning of how the research will lead to immediate next step studies in humans.
Comments will be accepted until May 15, 2019.
Note: Project duration is one year from the transfer of funds.
For additional questions about this funding opportunity, please contact Beth LaPensee at email@example.com.
For eligibility requirements, use of funds, and details on the application process, please see: