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Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.

ABSTRACT: Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at single-nucleotide polymorphism (SNP) rs2267735 within the PAC1 receptor gene (ADCYAP1R1) have increased symptoms of PTSD. This SNP is located within a predicted estrogen response element (ERE), which regulates gene transcription when bound to estradiol (E2) activated estrogen receptor alpha (ER?). In the current study, we examined E2 regulation of ADCYAP1R1 in vitro, in cell culture, and in vivo in mice and humans. We find in mice that fear conditioning and E2 additively increase ADCYAP1R1 expression. In vitro, we show that E2/ER? binds to the ADCYAP1R1 ERE, with less efficient binding to an ERE containing the C allele of rs2267735. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression, which further associates with higher PTSD symptoms. These findings lead to a model in which E2 induces the expression of ADCYAP1R1 through binding of ER? at the ERE as an adaptive response to stress. Inhibition of E2/ER? binding to the ERE containing the rs2267735 risk allele results in reduced expression of ADCYAP1R1, diminishing estrogen regulation as an adaptive stress response and increasing risk for PTSD.

SUBMITTER: Mercer KB

PROVIDER: S-EPMC5290337 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.

Mercer K B KB Dias B B Shafer D D Maddox S A SA Mulle J G JG Hu P P Walton J J Ressler K J KJ

Translational psychiatry 20161213 12

Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at sing ...[more]

PMID: 27959335

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Project description:RationaleGrowth arrest DNA damage inducible alpha (GADD45a) is a stress-induced gene we have shown to participate in the pathophysiology of ventilator-induced lung injury (VILI) via regulation of mechanical stress-induced Akt ubiquitination and phosphorylation. The regulation of GADD45a expression by mechanical stress and its relationship with acute lung injury (ALI) susceptibility and severity, however, remains unknown.ObjectivesWe examined mechanical stress-dependent regulatory elements (MSRE) in the GADD45a promoter and the contribution of promoter polymorphisms in GADD45a expression and ALI susceptibility.Methods and resultsInitial studies in GADD45a knockout and heterozygous mice confirmed the relationship of GADD45a gene dose to VILI severity. Human lung endothelial cells (EC) transfected with a luciferase vector containing the full length GADD45a promoter sequence (-771 to +223) demonstrated a >4 fold increase in GADD45a expression in response to 18% cyclic stretch (CS, 4 h) compared to static controls while specific promoter regions harboring CS-dependent MSRE were identified using vectors containing serial deletion constructs of the GADD45a promoter. In silico analyses of GADD45a promoter region (-371 to -133) revealed a potential binding site for specificity protein 1 (SP1), a finding supported by confirmed SP1 binding with the GADD45a promoter and by the significant attenuation of CS-dependent GADD45a promoter activity in response to SP1 silencing. Separately, case-control association studies revealed a significant association of a GADD45a promoter SNP at -589 (rs581000, G>C) with reduced ALI susceptibility. Subsequently, we found allelic variation of this SNP is associated with both differential GADD45a expression in mechanically stressed EC (18% CS, 4 h) and differential binding site of interferon regulatory factor 7 (IRF7) at this site.ConclusionThese results strongly support a functional role for GADD45a in ALI/VILI and identify a specific gene variant that confers risk for ALI.

Dataset Information

Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.

Publications

Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.

Similar Datasets

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