Arancibia Marcelo, Manterola Marcia, Ríos Ulises, Moya Pablo R, Moran-Kneer Javier, Bustamante M Leonor
Department of Psychiatry, Faculty of Medicine, School of Medicine, Universidad de Valparaíso, Valparaíso 2360002, Chile.
Center for Translational Studies in Stress and Mental Health (C-ESTRES), Faculty of Sciences, Universidad de Valparaíso, Valparaíso 2360102, Chile.
Genes (Basel). 2025 Mar 11;16(3):325. doi: 10.3390/genes16030325.
has been of special scientific interest in the behavioral sciences since it has been involved in the pathophysiology of several mental disorders. It is a gene with pleiotropic effects which encodes the protein FKBP5, a cochaperone that decreases glucocorticoid receptor (GR) affinity for glucocorticoids by competing with FKBP4, altering the GR chaperone complex, and impairing GR activation. As a key modulator of the stress response, FKBP5 plays a critical role in regulating cortisol levels in the organism. The gene is regulated through a combination of transcriptional, epigenetic, post-transcriptional, and environmental mechanisms, as well as genetic polymorphisms that influence its transcription and stress responsiveness. Notably, the rs1360780 T-allele in significantly affects FKBP5 regulation and has been linked to stress-related disorders by influencing transcription and stress responsiveness. In this narrative review, we aim to provide an overview of the role played by the single-nucleotide polymorphism rs1360780 in the locus in gene expression, its epigenetic regulation, and the impact of early stress in its functioning. We discuss some brain regions with differential expression of and some behavioral phenotypes linked to the locus. The T-allele of rs1360780 is considered a risk variant, as it leads to high induction, which delays negative feedback and increases GR resistance. This results in states of relative hypercortisolemia and brain morphofunctional alterations, particularly in regions sensitive to glucocorticoid activity during critical periods of neurodevelopment. Additionally, exposure to childhood maltreatment is associated with demethylation of the glucocorticoid response elements of , further increasing its expression levels. Among the psychological dimensions analyzed in which is involved are neurocognition, aggression, suicidality, and social cognition. At the level of mental disorders, the gene may play a role in the pathogenesis of post-traumatic stress disorder, depression, and bipolar disorder. In psychotic disorders, its role is less clear. This knowledge enhances the understanding of disease mechanisms that operate through psychopathological dimensions, and highlights the need to design specific, person-centered psychopharmacological and environmental therapeutic interventions.
自其参与多种精神障碍的病理生理学以来，它在行为科学中一直具有特殊的科学意义。它是一个具有多效性的基因，编码FKBP5蛋白，FKBP5是一种辅助伴侣蛋白，通过与FKBP4竞争、改变糖皮质激素受体（GR）伴侣复合物以及损害GR激活来降低GR对糖皮质激素的亲和力。作为应激反应的关键调节因子，FKBP5在调节机体皮质醇水平方面起着至关重要的作用。该基因通过转录、表观遗传、转录后和环境机制以及影响其转录和应激反应性的基因多态性的组合来调节。值得注意的是，rs1360780的T等位基因在[基因名称]中显著影响FKBP5调节，并通过影响转录和应激反应性与应激相关障碍有关。在这篇叙述性综述中，我们旨在概述单核苷酸多态性rs1360780在[基因名称]基因座中的作用，包括其在基因表达、表观遗传调控以及早期应激对其功能的影响。我们讨论了一些[基因名称]表达存在差异的脑区以及与该基因座相关的一些行为表型。rs1360780的T等位基因被认为是一个风险变异体，因为它会导致[基因名称]的高诱导，从而延迟负反馈并增加GR抗性。这会导致相对高皮质醇血症状态和脑形态功能改变，特别是在神经发育关键时期对糖皮质激素活性敏感的区域。此外，童年期受虐待与[基因名称]糖皮质激素反应元件的去甲基化有关，进一步增加其表达水平。在涉及[基因名称]的心理维度分析中，包括神经认知、攻击性、自杀行为和社会认知。在精神障碍层面，该基因可能在创伤后应激障碍、抑郁症和双相情感障碍的发病机制中起作用。在精神分裂症中，其作用尚不清楚。这些知识增强了我们对通过精神病理学维度起作用的疾病机制的理解，并强调了设计特定的、以患者为中心的心理药理学和环境治疗干预措施的必要性。
