Epigenetic DNA Variants Predictive of Coronary Artery Disease

MedicalResearch.com Interview with:

Stella Aslibekyan, PhD Associate Professor PhD Program Director Department of Epidemiology University of Alabama at Birmingham

Dr. Aslibekyan

Stella Aslibekyan, PhD
Associate Professor
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.

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Fatty Liver At Least Partially Mediated By Epigenetic Influences

MedicalResearch.com Interview with:

Annette Schürmann PhD Department of Experimental Diabetology German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) Nuthetal Germany German Center for Diabetes Research (DZD München-Neuherberg Germany

Dr. Annette Schürmann

Annette Schürmann PhD
Department of Experimental Diabetology
German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE)
Nuthetal
Germany German Center for Diabetes Research (DZD
München-Neuherberg Germany

MedicalResearch.com: What is the background for this study?

Response: The aim of our study was to clarify why genetically identical mice respond very different to a high fat diet. Some of the mice react with an elevated body weight, others not. We analyzed the expression pattern
of liver at two time points, at the age of 6 weeks, (the earlierst time
point to distiguish between those that respond to the diet (responder
mice) and those that did not (non-responders)), and at the age of 20
weeks. One transcript that was significantly reduced in the liver of
responder mice at both time points was Igfbp2. The reason for the
reduced expression was an elevated DNA-methylation at a position that is
conserved in the mouse and human sequence. The elevated DNA-methylation
of this specifc site in human was recently described to associate with
elevated fat storage (hepatosteatosis) and NASH. However, as 6 weeks old
mice did not show differences in liver fat content between responder and
non-responder mice we conclude that the alteration of Igfbp2 expression
and DNA metyhlation occurs before the development of fatty liver.

Our data furthermore showed that the epigenetic inhibition of Igfbp2
expression was associated with elevated blood glucose and insulin
resistance but not with fatty liver.

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Epigenetics, Not Just Genes, Control Many Complex Traits

Prof. Moshe Szyf Ph.D. James McGill Professor of Pharmacology and Therapeutics McGill UniversityMedicalResearch.com Interview with:
Prof. Moshe Szyf Ph.D.

James McGill Professor of Pharmacology and Therapeutics
McGill University


Medical Research: What is the background for this study? What are the main findings?

Dr. Szyf: Humans exhibit a marked variation in traits both physical and behavioral and different susceptibilities  for developing disease. What causes this inter-individual variation? The prevailing dogma has been that changes in the sequences of genes or heritable genetic differences are responsible for these  differences. We tested here an alternative hypothesis that perhaps some of the reason for this natural variation in traits is not caused by differences in inherited genes but by “epigenetic” changes that alter the way genes work without changing the genes.  The main difference between genetic and epigenetic changes is that epigenetic changes could be introduced by experience and exposure to environment. The experiences that can cause epigenetic changes include physical as well as social environments. Although we had known that epigenetic differences occur in humans and animals we didn’t have evidence that these changes are behind the natural variation in traits that is observed in humans and animals. Ants are an exciting biological paradigm that exhibits quantitative variations in size and therefore provided a unique opportunity to test this hypothesis.

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Folate Deficiency May Affect Subsequent Generations Through Epigenetics

Erica D. Watson, PhD Lecturer in Reproductive Biology Centre for Trophoblast Research Dept Physiology, Development and Neuroscience University of Cambridge Physiology Building, Downing Site Cambridge, CB2 3EG, United Kingdom MedicalResearch.com Interview with:
Erica D. Watson, PhD
Lecturer in Reproductive Biology Centre for Trophoblast Research Dept Physiology, Development and Neuroscience University of Cambridge, United Kingdom

MedicalResearch.com:  What are the main findings of the study?

Dr. Watson: It has been known for decades that maternal folate deficiency increases the risk for a diverse range of health problems in her children, such as spina bifida, heart defects and growth restriction. Despite this, the molecular mechanism of folate during development was not well understood. Our study is important because it shows that the inability to break down folate due to a mutation in the gene Mtrr can affect the health not only in the immediate offspring but also of the next generation.

We used mice for the study as they metabolize folate similarly to humans and because folic acid deficiency or mutations in the genes required to break down folate in humans result in similar developmental abnormalities and diseases in mice. This enabled us to explore how the molecular mechanism of folate deficiency impacted development, thereby causing health problems.

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Squamous Cell Carcinoma of Head and Neck: Epigenetic Markers

MedicalResearch.com Interview with:
Dr. Muy-Teck Teh BSc, PhD
Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry
Barts & The London School of Medicine and Dentistry
Queen Mary University of London, England, United Kingdom

MedicalResearch.com: What are the main findings of the study?

Answer: We found unique DNA markings (epigenetic methylation) on certain genes that may “predict” the risk of developing head and neck cancer. We identified certain DNA methylation marks unique to cancer cells and not found in normal healthy cells.

DNA methylation marks act as ‘switches’ that regulate the ‘on or off’ statuses of genes. Abnormal DNA methylation is known to precede cancer initiation. Hence, the presence of these abnormal DNA methylation marks in cells may be tell-tale signs of early cancer initiation. The chemically distinctive properties of methylated DNA provide ample opportunities for clinical exploitation as nucleic acid-based biomarkers potentially detectable in non-invasive samples such as blood, buccal scrapes, or even saliva.
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