Yin You, Liu Yan, Pan Xiao, Chen Rui, Li Peng, Wu Hui-Juan, Zhao Zheng-Qing, Li Yan-Peng, Huang Liu-Qing, Zhuang Jian-Hua, Zhao Zhong-Xin
Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Institute of Neuroscience and MOE Key Laboratory of Molecular Neurobiology, Neuroscience Research Center of Changzheng Hospital, The Second Military Medical University Shanghai, Shanghai, China.
PLoS One. 2016 Mar 3;11(3):e0149945. doi: 10.1371/journal.pone.0149945. eCollection 2016.
Sleep alleviates Alzheimer's disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33-14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13-2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.
睡眠可缓解与阿尔茨海默病（AD）相关的神经病理过程，而AD患者的睡眠障碍与外周炎症细胞因子水平升高有关。在本研究中，我们评估了白细胞介素（IL）-1β和载脂蛋白Eε4（APOEε4）基因多态性与AD患者睡眠障碍易感性的关联。连续招募了123例经过预处理的AD患者和120例年龄、性别及教育水平相匹配的健康对照者，进行连续两晚的全夜多导睡眠监测，并测量用于评估睡眠-觉醒障碍的爱泼华嗜睡量表（ESS）评分。使用连接酶检测反应（LDR）技术分析他们基因组DNA中的IL-1β和APOEε4单核苷酸多态性（SNP）。在脂多糖（LPS）刺激后，采用酶联免疫吸附测定法（ELISA）测量血液中IL-1β、IL-6和肿瘤坏死因子α（TNF-α）的水平。使用无条件逻辑回归模型计算特定基因型风险的比值比和95%置信区间，并按年龄、性别、教育水平、体重指数（BMI）和日常生活活动能力（ADL）进行校正。与非APOEε4/ε4基因型相比，APOEε4/ε4显著增加了患AD的风险（APOEε4/ε4与非APOEε4/ε4相比，校正后的比值比=4.33，95%置信区间=1.33-14.10，p=0.015）。与IL-1β CC基因型（-31）相比，TT基因型显著增加了患AD的风险（TT与CC相比，校正后的比值比=1.72，95%置信区间=1.13-2.61，p=0.010）。携带APOEε4等位基因和IL-1β TT基因型的AD患者比携带CC/CT组合基因型的患者在床上的时间更少、睡眠潜伏期和快速眼动睡眠潜伏期更长、觉醒次数更多且慢波睡眠百分比更低。此外，同时携带APOEε4等位基因和IL-1β -31TT基因型的AD患者血液中IL-1β水平显著高于携带APOEε4等位基因和-31 TC或CC基因型的患者。总之，本研究提供了首个证据，表明IL-1β -31TT基因型与纯合APOEε4共同作用会增加发生伴有睡眠障碍的AD的风险。
