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EBioMedicine. 2019 Feb;40:595-604. doi: 10.1016/j.ebiom.2019.01.041. Epub 2019 Jan 30.

Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival.

Author information

1
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: par.hallberg@medsci.uu.se.
2
Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
3
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Uppsala Clinical Research Center, Uppsala, Sweden.
4
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
5
Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
6
Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
7
Medical Products Agency, Uppsala, Sweden.
8
Department of Immunology, Genetics and Pathology, Medical Genetics and Genomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
9
Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract

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 × 10-8, 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 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, 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.

KEYWORDS:

(MeSH); Autoimmune diseases; Drug-related side effects and adverse reactions; Genetic variation; Genome-wide association study; Glial cell line-derived neurotrophic factor; H1N1 subtype; Influenza A virus; Influenza vaccines; Narcolepsy; Pharmacogenetics; RNA, long noncoding

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