Genomics and Epigenomics of Common Human Metabolic and Heart Disease
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Date
2015-02-11
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Johns Hopkins University
Abstract
The field of epigenetics is rapidly becoming recognized as playing an essential part in explaining common human disease. Here we probe DNA methylation in diabetes mellitus and associated metabolic phenotypes and coronary heart disease. In a cohort from the Framingham Heart Study, we use epidemiological techniques to identify over 20,000 CpGs differentially methylated in coronary heart disease patients. In the other chapters, we use a functional approach to investigate the epigenetics of Type 2 Diabetes (T2D) and combine three lines of evidence – diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and evidence of T2D clinical risk – to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass surgery, identifying regions where both the location and direction of methylation change is conserved. These regions overlap with 27 genomic locations with genetic T2D risk, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed five genes with novel roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk.
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Keywords
Epigenetics, diabetes, heart disease, DNA methylation, DNAm, insulin resistance, metabolism