中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (10): 1887-1893.doi: 10.4103/1673-5374.280322

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

中国汉族早发和晚发型发作性睡病患者临床特征和遗传特点的差异

  

  • 出版日期:2020-10-15 发布日期:2020-08-19
  • 基金资助:

    中央卫生专项基金研究项目（W2017BJ52）

Differences in clinical and genetic characteristics between early- and late-onset narcolepsy in a Han Chinese cohort

Hui Ouyang1, Fang Han2, Ze-Chen Zhou3, Jun Zhang1   

  1. 1 Department of Clinical Neurology, Peking University People’s Hospital, Beijing, China
    2 Department of Clinical Pulmonology, Peking University People’s Hospital, Beijing, China
    3 Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
  • Online:2020-10-15 Published:2020-08-19
  • Contact: Jun Zhang, zhangjun@pkuph.edu.cn.
  • Supported by:
    This study was supported by the Research Project of Central Health Care Special Fund, China, No. W2017BJ52 (to JZ).

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摘要：

发作性睡病分为早发型和晚发型睡病2类。中国早发型和晚发型发作性睡病患者在症状学和遗传风险是否存在差异，目前尚仍不清楚。此项病例-对照研究比较了中国汉族早发型和晚发型发作性睡病899例的临床资料和单核苷酸多态性(SNPs)变化。首先前瞻性地收集患者的血液、脑脊液和临床数据，并对其基因型进行筛选，筛选出40个以往文献报道的与发作性睡病相关的SNPs。基于遗传风险评分(GRS)，采用Logistic回归和受试者操作特征(ROC)曲线评价5组不同SNP(GRS1-5)与早发型发作性睡病的相关性。结果显示，(1) 平均睡眠潜：早发型发作性睡病患者平均睡眠潜伏期明显短于晚发型患者；(2)症状严重程度：晚发型患者睡瘫发生率、睡眠幻觉发生率、生活质量受损率，同时出现4种或4种以上症状的发生率均较早发型患者更高；(3)下丘脑分泌素水平：在早发型和晚发型发作性睡病患者间下丘脑分泌素水平无显著差异；(4)基因多态位点变化：早发病例中，rs3181077(CCR1/CCR3)和rs9274477(HLA-DQB1)多态位点变异更常见；(5)危险因素分析：GRS1(26个SNPs；OR=1.513，95%CI：0.893 to -2.585；P < 0.05)和GRS5(6个SNPs；OR=1.893，95%CI：1.204 to -2.993；P < 0.05)与早发型发作性睡病相关，ROC曲线下面积分别为0.731和0.732，GRS1和GRS5均不包括HLA区的SNP；(6)结果表明：中国汉族早发型和晚发型发作性睡病患者在临床特征和遗传特点方面存在差异。研究方案已于2011年10月获得北京大学人民医院行业审查委员会医学人体专家小组的批准(院伦审临医字第86号)。

orcid: 0000-0002-5726-7190 (Jun Zhang)

关键词: 病例-对照研究, 临床特征, 遗传关联研究, 遗传位点, 遗传负荷, 遗传现象, 下丘脑疾病, 神经变性, 单核苷酸多态性, 精准医学, 风险评估

Abstract: Early- and late-onset narcolepsy constitutes two distinct diagnostic subgroups. However, it is not clear whether symptomology and genetic risk factors differ between early- and late-onset narcoleptics. This study compared clinical data and single-nucleotide polymorphisms (SNPs) between early- and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients. Blood, cerebrospinal fluid, and clinical data were prospectively collected from patients, and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs. Genetic risk scores (GRSs), associations of five different sets of SNPs (GRS1–GRS5) with early- and late-onset narcolepsy, were evaluated using logistic regression and receiver operating characteristic curves. Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases. Symptom severity was greater among late-onset patients, with higher rates of sleep paralysis, hypnagogic hallucinations, health-related quality of life impairment, and concurrent presentation with four or more symptoms. Hypocretin levels did not differ significantly between early- and late-onset cases. Only rs3181077 (CCR1/CCR3) and rs9274477 (HLA-DQB1) were more prevalent among early-onset cases. Only GRS1 (26 SNPs; OR = 1.513, 95% CI: 0.893–2.585; P < 0.05) and GRS5 (6 SNPs; OR = 1.893, 95% CI: 1.204–2.993; P < 0.05) were associated with early-onset narcolepsy, with areas under the receiver operating characteristic curves of 0.731 and 0.732, respectively. Neither GRS1 nor GRS5 included SNPs in HLA regions. Our results indicate that symptomology and genetic risk factors differ between early- and late-onset narcolepsy. This protocol was approved by the Institutional Review Board (IRB) Panels on Medical Human Subjects at Peking University People’s Hospital, China (approval No. Yuanlunshenlinyi 86) in October 2011.

Key words: case-control studies, clinical features, genetic association studies, genetic load, genetic loci, genetic phenomena, hypothalamic diseases, precision medicine, risk assessment, single nucleotide polymorphism