06 Apr Epigenetic DNA Variants Predictive of Coronary Artery Disease
MedicalResearch.com Interview with:
Stella Aslibekyan, PhD
PhD Program Director
Department of Epidemiology
University of Alabama at Birmingham
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: When the human genome was sequenced in 2003, there were somewhat unrestrained expectations of unraveling all etiologic mysteries and discovering breakthrough treatments. Needless to say, that did not happen, in part because individual genetic variants can only account for a small fraction of trait variability. Since then, epigenetics– the study of mitotically heritable changes in gene expression– has emerged as another promising avenue for understanding disease risk. The best studied epigenetic process in humans is DNA methylation, and earlier studies (including some from our group) have shown interesting associations between changes in methylation in specific genomic regions and cardiovascular disease traits, e.g. plasma cholesterol levels.
In this project, we have combined DNA methylation data on thousands of individuals from multiple international cohorts and interrogated epigenetic contributions to circulating tumor necrosis factor alpha (TNFa), a marker of systemic inflammation. We identified and replicated several epigenomic markers of TNFa, linked them to variation in gene expression, and showed that these methylation changes (which were located in interferon pathway genes) were predictive of coronary heart disease later in life. Interestingly, the variants we discovered were not sequence-dependent (in other words, they were not associated with any genetic mutations), highlighting the role of the environment.
MedicalResearch.com: What should readers take away from your report?
Response: Epigenetic processes such as DNA methylation represent a promising target for future therapeutic or risk stratification efforts across a variety of phenotypes, including heart disease traits. Furthermore, our findings underscore the already known link between inflammation and heart disease, and suggest it could be mediated by DNA methylation.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Since this was an observational study, it will be important to validate our findings in a rigorous experimental context, for example using gene editing or knockout models. It is especially important because we do not know if the changes in DNA methylation can help predict disease onset or are merely indicative of disease processes that are already underway yet are clinically undetectable; despite the prospective design, the chicken vs. the egg question remains unresolved. Upon experimental validation, our findings can be used in the drug development process or to identify individuals at higher risk for coronary heart disease.
MedicalResearch.com: Is there anything else you would like to add?
Response: This research would not have been possible without of support of the National Institutes of Health. Full information on disclosures is available in the main article on the JAMA Network website.
Aslibekyan S, Agha G, Colicino E, et al. Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α. JAMA Cardiol. Published online April 04, 2018. doi:10.1001/jamacardio.2018.0510
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