Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Nature. 2011 Feb 24;470(7335):492-7. doi: 10.1038/nature09856.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
垂体腺苷酸环化酶激活肽 (PACAP) 被广泛认为可调节细胞应激反应。相比之下，PACAP-PAC1 受体通路是否在人类心理应激反应（如创伤后应激障碍 (PTSD)）中发挥作用尚不清楚。在这里，我们发现，在遭受重创的受试者中，PACAP 血液水平与恐惧生理学、女性 PTSD 诊断和症状之间存在性别特异性关联。我们研究了横跨 PACAP（由 ADCYAP1 编码）和 PAC1（由 ADCYAP1R1 编码）基因的 44 个单核苷酸多态性 (SNP)，结果表明这些 SNP 与 PTSD 存在性别特异性关联。ADCYAP1R1 内一个假定的雌激素反应元件中的单个 SNP（rs2267735）仅预测女性的 PTSD 诊断和症状。该 SNP 还与恐惧辨别以及人类大脑中的 ADCYAP1R1 信使 RNA 表达相关联。ADCYAP1R1 在外周血中的甲基化也与 PTSD 相关。这些人类数据的补充结果表明，PACAP-PAC1 通路的扰动与 PTSD 下的异常应激反应有关。这些性别特异性效应可能是通过雌激素对 ADCYAP1R1 的调节而发生的。PACAP 水平和 ADCYAP1R1 SNP 可作为有用的生物标志物，进一步深入了解 PTSD 的发病机制。
