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Clin Epigenetics. 2018 Jun 19;10:82. doi: 10.1186/s13148-018-0513-0. eCollection 2018.

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

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1Departments of Internal Medicine & Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Harvey Bldg. Rm 805, Baltimore, MD 21287 USA.
2Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Ohio State University Wexner Medical Center, 566 McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210 USA.
3Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 720 Rutland Ave. Ross Bldg. 1068, Baltimore, MD 21205 USA.
4Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street Suite 333, Baltimore, MD 21287 USA.



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.


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).


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.


Body mass index (BMI); Cardiovascular disease; Cortisol; Diabetes; Epigenetics; FKBP5; Hemoglobin A1c; Methylation; Obesity; Waist circumference

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