Type 2 diabetes and cardiometabolic risk may be associated with increase in DNA methylation of FKBP5

Background: Subclinical hypercortisolism and hypothalamic-pituitary-adrenal (HPA) axis dysfunction are associated with type 2 diabetes (T2DM), cardiovascular disease, and metabolic dysfunction. Intronic methylation of FKBP5 has been implicated as a potential indicator of chronic cortisol exposure. Our overall objective in this study was to determine the association of chronic cortisol exposure, measured via percent methylation of FKBP5 at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM. Results: Greater percent methylation of the FKBP5 intron 2 at one CpG-dinucleotide region was significantly associated with higher HbA1c (β = 0.535, p = 0.003) and LDL cholesterol (β = 0.344, p = 0.037) and a second CpG-dinucleotide region was significantly associated with higher BMI and WC (β = 0.516, p = 0.001; β = 0.403, p = 0.006, respectively). Conclusions:FKBP5 methylation may be a marker of higher metabolic risk in T2DM, possibly secondary to higher exposure to cortisol. Further work should aim to assess the longitudinal association of FKBP5 with cardiovascular disease and glycemic outcomes in T2DM as a first step in understanding potential preventive and treatment-related interventions targeting the HPA axis.