The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure.
The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure.
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DOI：
10.1111/gbb.12342
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Goldman D
中科院分区：
文献类型：
--
作者：
Yeo S;Enoch MA;Gorodetsky E;Akhtar L;Schuebel K;Roy A;Goldman D
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 expression of glucocorticoid-regulated genes including FKBP5, we used lymphoblastoid cell lines (LCLs) derived from 16 CT-exposed patients with ≥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 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 due to 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 ultrashort 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. Childhood trauma exposure appears to be essential for trans-effects of rs1360780 on glucocorticoid-regulated genes.
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通讯作者：
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