Cardiovascular disease is the leading cause of death in the United States. Prevention efforts can be costly or carry potential side effects and therefore are often directed based on predicted risk. However, there are major gaps in our ability to predict who will develop overt coronary heart disease or antecedent atherosclerotic and cardiometabolic disease. The health of millions of Americans is potentially affected, as lifesaving therapeutics are withheld unnecessarily or unneeded medications prescribed. Accurately predicting coronary heart disease risk is an especially vexing problem in young adults in whom low short-term risks often belie elevated lifetime hazards. Better biomarkers of risk are needed for the development of personalized cardiovascular disease prevention approaches. Recognition of the role of the epigenome in chronic disease has opened new avenues for clinical biomarker discovery. Methylation of cytosine-phosphate dinucleotides, one of the most well studied and characterized epigenetic modifications, influences gene expression without changing the underlying genetic sequence. DNA methylation reflects at the molecular level a wide range of environmental and genetic factors that may have been shaped by intergenerational and lifetime influences. The ability to study DNA methylation as a biomarker was made possible only recently by high throughput assays on thousands of individuals from deeply phenotyped disease cohorts. The proposed project will utilize rigorous evaluation methods to determine the clinical validity of DNA methylation biomarkers to predict coronary heart disease, subclinical atherosclerosis, and cardiometabolic disease in the Framingham Heart Study. In an independent pediatric cohort, the clinical utility will be examined in the context of evaluating how lifestyle interventions modify epigenetic-predicted risk and whether DNA methylation biomarkers can predict who will respond to a lifestyle modification intervention. DNA methylation biomarkers will be evaluated using a lifecourse approach ranging from adolescents to older adults. The candidate for this career development award, Dr. Michael Mendelson, is a pediatric cardiologist with a Masters of Science degree in epidemiology and experience in cardiovascular disease epidemiology and population-based DNA methylation studies. In order to achieve scientific independence for the candidate, a comprehensive career development program has been developed to gain additional needed training in the areas of: 1) statistical coding and bioinformatics, 2) advanced risk prediction methods, and 3) state-of-the-art epigenetic mechanisms. This will be accomplished through coursework and seminars, under the mentorship of leaders in the field of genetic epidemiology (Joel Hirschhorn), cardiovascular disease epidemiology (Daniel Levy), and risk prediction (Ralph D'Agostino Sr.), with regular progress monitoring by an advisory committee.

Public Health Relevance

Improved risk prediction, based on an individual's epigenome, can help direct heart disease prevention efforts toward those who would benefit most. We seek to determine if combining traditional clinical risk models with DNA methylation profiles from blood samples will improve our ability to predict who will develop heart disease and its risk factors. We will also determine how changing lifestyle behaviors affect heart disease-related epigenetic modifications and the ability of epigenetic biomarkers to predict who will respond to a prevention intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL136875-02
Application #
9457223
Study Section
NHLBI Mentored Transition to Independence Review Committee (MTI)
Program Officer
Srinivas, Pothur R
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Mendelson, Michael M; Johannes, Roby; Liu, Chunyu et al. (2018) Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study. Front Pharmacol 9:207
Yao, Chen; Chen, George; Song, Ci et al. (2018) Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease. Nat Commun 9:3268
Marioni, Riccardo E; McRae, Allan F; Bressler, Jan et al. (2018) Meta-analysis of epigenome-wide association studies of cognitive abilities. Mol Psychiatry 23:2133-2144
Story Jovanova, Olivera; Nedeljkovic, Ivana; Spieler, Derek et al. (2018) DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons: Meta-analysis of Multiethnic Epigenome-wide Studies. JAMA Psychiatry 75:949-959
Desai, Nirav K; Mendelson, Michael M; Baker, Annette et al. (2018) Hepatotoxicity of Statins as determined by Serum Alanine Aminotransferase in a Pediatric Cohort with Dyslipidemia. J Pediatr Gastroenterol Nutr :
Aslibekyan, Stella; Agha, Golareh; Colicino, Elena et al. (2018) Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor ?. JAMA Cardiol 3:463-472
Mendelson, Michael M (2018) Epigenetic Age Acceleration: A Biological Doomsday Clock for Cardiovascular Disease? Circ Genom Precis Med 11:e002089
Liu, C; Marioni, R E; Hedman, Å K et al. (2018) A DNA methylation biomarker of alcohol consumption. Mol Psychiatry 23:422-433
Yao, Chen; Chen, George; Song, Ci et al. (2018) Author Correction: Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease. Nat Commun 9:3853
Weinrauch, Larry A; Gerhard-Herman, Marie D; Mendelson, Michael M (2018) Epigenetics: Is the Mode of Conception a Marker for Future Cardiovascular Risk? J Am Coll Cardiol 72:1275-1277

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