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首页> 外文期刊>EBioMedicine >Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
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Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival

机译：Pandemrix引起的发作性睡病与免疫力和神经元存活相关的基因有关

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Background The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy. Methods We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p ??5?×?10sup?8/sup, and the nominal threshold was p ??0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation. Findings Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p ?=?7.9?×?10sup?9/sup. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR?=?8.7 [95% CI 4.2, 17.5], p ?=?2.6?×?10sup?9/sup, and this was replicated, OR?=?3.4 [95% CI 1.2–9.6], p ?=?0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR?=?2.0 [95% CI 1.4, 2.8], p ?=?0.0002. Interpretation We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.
机译：背景在使用Pandemrix接种甲型H1N1猪流感疫苗后，发作性睡病的发病率急剧上升。发作性睡病是一种与免疫有关的疾病，白天嗜睡。最常见的形式与HLA-DQB1 * 06：02密切相关，但只有少数携带者会发作发作性睡病。我们旨在确定易患Pandemrix发作性发作性睡病的遗传标记。方法我们测试了42例嗜睡症患者和4981名对照的全基因组和候选基因关联。在Illumina阵列上进行基因分型，使用SNP2HLA推算HLA等位基因，并使用单倍型参考协会面板推算单核苷酸多态性。全基因组显着性阈值为p≤<5 5××10 10 ≤8，标称阈值为p≤<0.05。将结果复制到32例病例和7125例对照中。染色质数据用于功能注释。携带HLA-DQB1 * 06：02的结果与发作性睡病显着相关，优势比（OR）39.4 [95％置信区间（CI）11.3，137]，p == 7.9？×？10 ？9 。调整HLA后，GDNF-AS1（rs62360233）显着相关，或？== 8.7 [95％CI 4.2，17.5]，p == 2.6？×？10 ？9 ，重复进行OR ＝＝ 3.4 [95％CI 1.2-9.6]，p ＝＝ 0.022。功能分析显示高LD的rs62360233变异可能解释了检测到的关联。候选免疫基因位点TRAJ（rs1154155）在发现和复制队列中都具有名义上的联系，荟萃分析OR == 2.0 [95％CI 1.4，2.8]，p == 0.0002。解释我们发现了Pandemrix引起的发作性睡病与非编码RNA基因GDNF-AS1之间存在新的关联，该关联已被证明可以调节必需神经营养因子GDNF的表达。 GDNF调节的变化与神经退行性疾病有关。这一发现可能会增加对发作性睡病潜在疾病机制的了解。复制了Pandemrix诱发的发作性睡病与免疫相关基因之间的关联。

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