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Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0003-3465-3280
Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0002-2152-4343
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
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2019 (engelsk)Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 40, s. 595-604Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2019. Vol. 40, s. 595-604
Emneord [en]
(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
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-377169DOI: 10.1016/j.ebiom.2019.01.041ISI: 000460696900067PubMedID: 30711515OAI: oai:DiVA.org:uu-377169DiVA, id: diva2:1288998
Forskningsfinansiär
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningSwedish Research Council, 2017-00641Tilgjengelig fra: 2019-02-15 Laget: 2019-02-15 Sist oppdatert: 2019-05-13bibliografisk kontrollert

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