title: The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure.
abstract: The FK506 binding protein 51 (FKBP5), an intrinsic regulator of the glucocorticoid receptor, has been associated with pathological behaviors particularly in the context of childhood trauma (CT), via a putatively regulatory polymorphism, rs1360780. However, trans- and cis-acting effects of this locus and its interaction with CT are incompletely understood. To study its effects on the expression of glucocorticoid-regulated genes including FKBP5, we used lymphoblastoid cell lines (LCLs) derived from 16 CT-exposed patients with greater than two substance dependence/suicidal behavior diagnoses (casesCT+) and 13 non-CT-exposed controls (controlsCT-). This study in LCLs measures long-term trait-like differences attributable to genotype or lasting epigenetic modification. Through analysis of differential allelic expression (DAE) using an FKBP5 3'-UTR reporter single nucleotide polymorphism (SNP), rs3800373, that is in strong linkage disequilibrium with rs1360780, we confirmed that the rs1360780 risk allele (A) (or conceivably that of a linked SNP) leads to higher FKBP5 expression in controlsCT-. Intriguingly, casesCT+ did not show DAE, perhaps because of a genotype-predicted difference in FKBP5 DNA methylation restricted to casesCT+. Furthermore, through correlation analyses on FKBP5 expression at baseline and after induction by dexamethasone, we observed that casesCT+ had lower induction of FKBP5 expression, indicating that overall they may have strong ultra-short negative-feedback. Only casesCT+ showed an effect of rs1360780 genotype on expression of FKBP5 and other glucocorticoid-regulated genes. Together, these results confirm that the rs1360780 locus alters FKBP5 expression and further that in trans-fashion this locus affects the expression of other glucocorticoid-regulated genes after a glucocorticoid challenge. The CT exposure appears to be essential for trans-effects of rs1360780 on glucocorticoid-regulated genes.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: S
authors.initials: S
authors.lastname: Yeo
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: M-A
authors.initials: MA
authors.lastname: Enoch
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: E
authors.initials: E
authors.lastname: Gorodetsky
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: L
authors.initials: L
authors.lastname: Akhtar
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: K
authors.initials: K
authors.lastname: Schuebel
authors.affiliation: Psychiatry Service, Department of Veterans Affairs, New Jersey VA Health Care System, East Orange, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Roy
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: D
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000328:Adult; D002460:Cell Line; D019175:DNA Methylation; D003907:Dexamethasone / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014947:Wounds and Injuries / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003907:Dexamethasone; D005938:Glucocorticoids; D006854:Hydrocortisone; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: DNA methylation; FKBP5; cis-Acting regulation; differential allelic expression; glucocorticoid; glucocorticoid receptor; rs1360780; trans-acting effect; trauma; ultra-short negative-feedback