基于素质-应激模型的乳腺癌患者抑郁纵向变化模式及异质性机制研究

Depression is prevalent in breast cancer patients. Long-term depression could have negative influence on quality of life and disease outcome. It is important to explore the trajectory and heterogeneous change pattern of depression as well as its mechanisms in the process of disease diagnosis, treatment and rehabilitation. The diathesis-stress model focused on interplay effect of genetic predisposition and stress in the development of depression. Preliminary research revealed that oxytocin receptor gene polymorphism is associated with depression, but the results still lack consistency because of the neglect of gene and environment interaction as well as potential racial differences. Moreover, most of current studies use cross-sectional design and based on Caucasian sample. Previous studies of the applicant in Chinese adolescents have found that the oxytocin receptor gene polymorphism is associated with higher level of aggressive behaviors. The present project aims to reveal the trajectory and heterogeneous change pattern of depression in the process of disease diagnosis, treatment and rehabilitation. Furthermore, the project intends to explore the interplay effect of oxytocin receptor genes polymorphism and stress in the development of depression in breast cancer. Findings generated from the proposed study would improve understanding of the important time node of change in depression among breast cancer patients and contribute to identifying the genetic and environmental factors associated with high-risk groups for chronic depression and carrying out precise treatment and intervention.

乳腺癌患者高发抑郁，长期慢性抑郁对患者生活质量和疾病结局具有消极影响。全面剖析乳腺癌患者在疾病诊疗康复过程中抑郁的纵向变化特点及异质性，并解析其机制是重要科学问题。素质-应激模型关注遗传素质与应激对抑郁的共同作用。国外研究初步发现OXTR基因多态性与抑郁有关，但仍缺乏一致结论，可能与未考虑基因与环境共同作用以及种族差异有关。现有研究多基于国外样本，且多采用横断面设计，鲜见OXTR基因与抑郁纵向变化关系的探讨。申请人前期在中国青少年中的研究发现，OXTR基因与高应激水平下的社会行为异常有关。综合生命科学进展和前期研究基础，本项目拟采用纵向追踪设计，剖析乳腺癌患者抑郁的纵向变化特点及异质性，并基于素质-应激模型，解析OXTR基因与应激对抑郁发展变化的影响。本项目对识别乳腺癌患者抑郁发展变化的重要节点、鉴别抑郁高危进展人群、识别与抑郁高危进展相关联的遗传和环境因素，并开展精准化干预具有重要意义。

抑郁在乳腺癌患者中高发，长期慢性抑郁对患者生活质量和疾病结局具有消极影响。素质-应激模型关注遗传素质和应激对抑郁的共同作用。国外研究初步发现OXTR基因多态性与抑郁有关，但仍缺乏一致结论。本研究选取与疾病诊疗过程相关的时间点，对患者的抑郁症状进行多时间点追踪，剖析抑郁在诊断后随时间发展变化，并基于素质-应激模型，选取OXTR多个位点的单核苷酸多态性构建遗传风险评分（GRS），选取生活事件作为环境因素，考察二者在乳腺癌患者抑郁随时间发展变化中发挥的可能作用。本项目执行期间，构建了乳腺癌患者应激与心理行为健康队列，形成了乳腺癌应激与心理行为健康相关基因的生物样本库，明确了乳腺癌患者诊疗过程中抑郁的变化模式，并基于素质-应激模型，初步探索了乳腺癌抑郁相关的应激、遗传等因素。研究结果发现，乳腺癌患者抑郁呈现四种不同的变化模式：第一类别的患者持续存在低水平的抑郁；第二类型的患者持续中等水平的抑郁；第三类型的患者抑郁症状在后期呈上升趋势；第四类型的患者抑郁症状在前期呈上升趋势，随后有所下降。研究发现，OXTR基因GRS与应激的交互作用对抑郁症状有显著影响，即携带更多易感等位基因的患者在应激环境中会出现更高水平的抑郁症状。该结果符合素质‒应激理论模型，即携带风险基因的个体更容易受到不良环境因素的影响而产生心理或行为问题。本研究的结果对阐明乳腺癌患者抑郁的发生发展及相关的遗传和环境危险因素，进而针对性的减轻患者心理问题具有重要的理论和现实意义。

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