Fig. 2

The hypothesized relationship of FKBP5 DNA methylation and cardiometabolic risk. Our findings demonstrate evidence that FKBP5, and therefore likely the hypothalamic-pituitary-adrenal axis, play a role in metabolic and cardiovascular disease risk and outcome. FKBP5, and the glucocorticoid receptor, is expressed in the brain, intestinal endothelial, and epithelial tissues. FKBP5 expression in the brain (hypothalamus and hippocampus) as well as these other tissues has been associated previously with the influences of stress and cortisol load, exercise, and diet. Prior demonstration has also shown the function of FKBP5 to play a role in adipogenesis and in endothelial changes in myocardial infarction. Taken together, these associations are hypothesized to link to risk and outcomes in cardiometabolic disease through methylation of FKBP5, and therefore, potentially expression or sensitivity of the glucocorticoid receptor. The methylation of FKBP5 is associated with increased clinical risk factors for disease including hyperlipidemia (elevated LDL), chronic hyperglycemia (elevated HbA1c), and obesity (high BMI and WC) in individuals with diabetes. Further, methylation of FKBP5 may be associated with cardiovascular procedures and inversely associated with exercise independent of LDL and obesity. Though many clinical trials have established the classical model of pathophysiologic associations with diabetes and hyperglycemia, hyperlipidemia, obesity, and cardiometabolic disease, the findings illustrated here demonstrate that there may be a role for the hypothalamic-pituitary-adrenal axis and glucocorticoid pathway dysfunction in the underlying pathophysiology of cardiometabolic disease risk and outcomes