Figure 1.

Hypothesis tested in this study. Exposure to physiological challenges, such as an increased BMI, smoking or dysregulated glycemic control leads physiological changes that translate into changes in intermediate molecular phenotypes, such as metabolite levels that are detectable in different body fluids, blood circulating lipids, proteins and protein glycosylation. These then further induce changes in DNA methylation at specific regulatory sites of genes that are required to counter this insult. Note that this view does not exclude that changes in the expression of certain genes may not also result in further changes in molecular phenotypes. Hence, despite the fact that we found here three cases of causality from metabolite to CpG, cases with reverse directionality are also likely to exist.