Childhood Adverse Events and Their Correlation with FKBP5，ACTH，BDNF，and Cortisol in Susceptible and Resilient Drug-Using Populations
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摘要:
目的 探讨童年期负性事件与不良健康结局的关联，比较在童年期负性事件暴露下易感与弹性个体在FKBP5、ACTH、皮质醇、BDNF的差异。 方法 基于前期2021年1～7月建立的云南省405例吸毒人群的队列，采用巢式病例对照研究，检测对照组、弹性组及易感组的FKBP5、ACTH、皮质醇和BDNF水平；采用全基因组测序（whole genome sequencing，WGS）技术确定突变位点；运用SPSS 24.0和RStudio 4.3.1进行统计描述及多因素分析。 结果 对照组（n = 7）与弹性组（n = 14）的FKBP5水平存在显著差异[（4.67±1.08） vs. （6.86±1.87） ng/mL，P < 0.05]。与对照组相比，易感组（n = 14）的ACTH水平升高[（54.05±8.75） pg/mL，P < 0.05]；与易感组相比，弹性组的ACTH水平升高[（67.28±8.36） pg/mL，P < 0.05]。皮质醇水平在对照组与易感组[（254.92±70.46） vs. （278.50±49.60） nmol/L，P < 0.05]以及易感组与弹性组[（278.50±49.60） vs. （406.27±72.07） nmol/L，P < 0.05]之间均存在显著差异。多元Logistic回归分析显示，以对照组为参照，弹性组的FKBP5、皮质醇及rs34224676基因型水平均存在显著差异（OR = 3.62，95%CI：1.36～9.64，P < 0.05；OR = 1.02，95%CI：1.00～1.04，P < 0.05；OR = 185.34，95%CI：69.56～493.83，P < 0.05）。 结论 有ACEs暴露的吸毒人群FKBP5、ACTH和皮质醇水平高于无ACEs暴露者。在ACEs暴露下，吸毒人群中FKBP5、皮质醇及SNPs位点rs34224676的表达可能与弹性现象有关。 Abstract:Object To investigate the association between adverse childhood experiences （ACEs） and adverse health outcomes （AHOs）, and to compare the levels of FKBP5, ACTH, cortisol, and BDNF between susceptible and resilient individuals exposed to ACEs during childhood. Methods Based on a cohort of 405 individuals with substance use disorder in Yunnan Province established from January to July 2021, a nested case-control study was conducted. FKBP5, ACTH, cortisol, and BDNF levels were detected in the control group, resilient group and susceptible group. Whole-genome sequencing （WGS） technology was used to identify mutation sites Descriptive, univariate and multivariate analyses were conducted using SPSS 24.0 and R Studio version 4.3.1.n Results Significant differences in FKBP5 levels were found between the control group （n = 7） and resilient groups （n = 14） [（4.67±1.08） vs. （6.86±1.87） ng/mL, P < 0.05]. Compared with the control group, ACTH levels in the susceptible group （n = 14） were elevated [（54.05±8.75） pg/mL, P < 0.05]; compared with the susceptible group, ACTH levels in the resilient group were elevated [（67.28±8.36） pg/mL, P < 0.05]. Cortisol levels showed significant differences between the control and susceptible groups [（254.92±70.46） vs. （278.50±49.60） nmol/L, P < 0.05] and between the susceptible and resilient groups [（278.50±49.60） vs. （406.27±72.07） nmol/L, P < 0.05]. Multivariate logistic regression analysis showed that, with the control group as reference, the resilient group had significant differences in FKBP5, cortisol, and rs34224676 genotype levels （OR = 3.62, 95%CI: 1.36～9.64, P < 0.05; OR = 1.02, 95%CI: 1.00～1.04, P < 0.05; OR = 185.34, 95%CI: 69.56～493.83, P < 0.05）. Conclusion Individuals with substance use disorder exposed to ACEs exhibited higher levels of FKBP5, ACTH, and cortisol compared to those without ACEs exposure. Under ACEs exposure, the expression of FKBP5, cortisol, and the SNP locus rs34224676 in individuals with substance use disorder may be associated with the resilience phenomena. -
Key words:
- Adverse childhood experiences /
- FKBP5 /
- ACTH /
- Resilience /
- Susceptibility
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图 2 基于Fisher精确检验的曼哈顿图
A：对照组和其他组比较；B：易感组与弹性组比较；C：对照组和其他组间差异显著的基因位点；D：易感组与弹性组差异显著的基因位点。
Figure 2. Manhattan plot based on the Fisher exact test
图 3 多分类模型的微平均ROC曲线
Figure 3. Micro-average ROC curve of the multi-classification model
表 1 对照组、弹性组和易感组中社会人口学特征分析[n（%）]
Table 1. Sociodemographic characteristics in the control，resilient and susceptibility groups[n（%）]
变量 总计 单因素分析 多元Logistic回归 对照组 弹性组 易感组 P 弹性组（Ref.对照组） P 易感组（Ref.对照组） P （n=7） （n=14） （n=14） OR（95%CI） OR（95%CI） 毒品种类 0.671 0.606 0.831 安非他命类 33（94.3） 6（85.7） 13（92.9） 14（100） Ref. Ref. 阿片类/其他 2（5.7） 1（14.3） 1（7.1） 0 0.462（0.025，8.700） 0.001（0.00，1.139） 使用年限（年） 0.254 0.135 0.744 <10 19（54.3） 5（71.4） 5（35.7） 9（64.3） Ref. Ref. ≥10 16（45.7） 2（28.6） 9（64.3） 5（35.7） 4.501（0.627，32.301） 1.389（0.194，9.970） 使用频率 0.613 0.355 0.355 每月1次/更少 21（60.0） 3（42.9） 9（64.3） 9（64.3） Ref. Ref. 每周2～6天/每天 14（30.0） 4（57.1） 5（35.7） 5（35.7） 0.417（0.065，2.660） 0.417（0.065，2.660） 使用方式 1.000 1.000 1.000 烫吸/抽吸/嗦吸 25（71.4） 5（71.4） 10（71.4） 10（71.4） Ref. Ref. 吞咽/其他 10（28.6） 2（28.6） 4（28.6） 4（28.6） 0.999（0.134，7.451） 0.999（0.134，7.451） 饮酒 0.228 0.694 0.323 否 31（88.6） 6 （85.7） 14 （100） 11 （78.6） Ref. Ref. 是 4（11.4） 1（14.3） 0 3（21.4） 0.822 （0.308，2.190） 0.610 （0.229，1.625） 婚姻状况 0.602 0.004* <0.001* 未婚/离异/未知 6（17.1） 0 3（21.4） 3（21.4） Ref. Ref. 已婚/有配偶 29（82.9） 7（100） 11（78.6） 11（78.6） 4.185 （1.571，11.151） 38.080 （14.292，101.462） 经济来源 0.296 0.463 0.600 工作收入 21（60.0） 5 （71.4） 6 （42.9） 10 （71.4） Ref. Ref. 他人救济 14（40.0） 2 （28.6） 8 （57.1） 4 （28.6） 0.693 （0.260，1.846） 1.300 （0.488，3.463） 育有子女 0.684 0.550 <0.001* 无 9（25.7） 1 （14.3） 3 （21.4） 5 （35.7） Ref. Ref. 有 26（74.3） 6 （85.7） 11（78.6） 9（64.3） 1.348 （0.506，3.592） 0.092 （0.035，0.246） 安全套的使用 0.671 <0.001* 0.117 从未/偶尔使用 2（5.7） 1 （14.3） 1 （7.1） 0 Ref. Ref. 每次使用 33（94.3） 6 （85.7） 13（92.9） 14（100） 0.106 （0.040，0.281） 0.457 （0.171，1.217） 多性伴模式 0.002* 0.635 <0.001* 否 24（68.6） 4 （57.1） 14 （100） 6 （42.9） Ref. Ref. 是 11（31.4） 3（42.9） 0 8（57.1） 0.789 （0.296，2.101） 21.663 （8.130，57.719） 注：单因素分析采用Fisher确切概率法；*P < 0.05。 
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表 2 三个组的FKBP5、ACTH、皮质醇和BDNF水平差异分析
Table 2. Differences in FKBP5，ACTH，cortisol，and BDNF levels among the three groups
变量 总计 单因素分析 多因素分析 对照组 弹性组 易感组 P 弹性组
（Ref. 对照组）P 易感组
（Ref. 对照组）P （n=7） （n=14） （n=14） OR（95%CI） OR（95%CI） FKBP5 5.83 ± 1.86 4.67 ± 1.08 6.86 ± 1.87 5.38 ± 1.79 0.015*# 4.05（3.87，4.25） <0.001* 2.69（0.80，9.07） 0.111 ACTH 59.12 ± 11.94 52.96 ± 15.23 67.28 ± 8.36 54.05 ± 8.75 0.002*▲ 0.95（0.22，4.07） 0.949 1.07（0.79，1.43） 0.672 皮质醇 324.89 ± 91.78 254.92 ± 70.46 406.27 ± 72.07 278.50 ± 49.60 <0.001*#▲ 1.24（1.15，1.33） <0.001* 1.04（0.99，1.09） 0.170 BDNF 10.24 ± 2.39 9.37 ± 2.77 11.78 ± 2.33 9.15 ± 1.34 0.005*▲ 0.53（0.42，0.67） <0.001* 0.29（0.04，1.99） 0.206 注：单因素分析采用方差分析；对照组与弹性组相比#P < 0.05；弹性组与易感组相比▲P < 0.05；*P < 0.05；本研究样本量较小，采用Firth偏倚校正逻辑回归进行分析。
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表 3 弹性组与易感组多元Logistic回归模型
Table 3. Multivariate Logistic regression model for the resilient and susceptible group
变量 弹性组（Ref. 对照组）a P 易感组（Ref. 对照组）a P OR（95%CI）b OR（95%CI）b 社会人口学特征 0.828 <0.001* 安全套的使用 从未/偶尔使用 Ref. Ref. 每次使用 0.90（0.33～2.39） 0.19（0.07～0.51） 血液指标 FKBP5 3.62（1.36～9.64） <0.001* 1.53（0.57～4.07） 0.301 皮质醇 1.02（1.00～1.04） 0.032* 0.99（0.38～2.66） 0.968 SNP 位点 <0.001* 0.027* rs34224676 无 Ref. Ref. 有 185.34（69.56～493.83） 17.58（6.60～46.84） 注：a以对照组作为参考；b本研究样本量较小且数据完全删失，因此采用Firth偏倚校正逻辑回归进行分析；*P < 0.05。
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