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

Abstract

BackgroundThe 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.MethodsWe 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.FindingsCarrying 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.InterpretationWe 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.

HLA high-resolution typing by next-generation sequencing in Pandemrix-induced narcolepsy

“…The Pandemrix-vaccination in Sweden and Finland following the 2009 influenza pandemic resulted in an up to 15-fold increased incidence of NT1 in both countries [16–21]. Moreover, an increased incidence of NT1 was reported in China following the 2009 influenza pandemic [22, 23].…”

SWEDEGENE—a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions

“…However, for most ADRs comparisons are made with the 5000 populations controls with genome-wide data and 1000 with wholegenome sequencing data from TwinGene. GWAS of agranulocytosis induced by antithyroid drugs or sulfasalazine, cough induced by angiotensin-converting enzyme (ACE) inhibitors, narcolepsy induced by Pandemrix and atypical femoral fractures induced by bisphosphonates have been published [18][19][20][21][22]. SWEDEGENE has also provided cases and controls in several other collaborative studies, such as GWAS and whole exome sequencing of statin In addition to the below numbers, a total of 580 drug-treated controls have been recruited induced myopathy [23,24], drug induced liver toxicity [25][26][27][28][29][30], and hypersensitivity reactions to carbamazepine [31].…”

“… 1) Fractures of the femoral neck, intertrochanteric fractures with spiral subtrochanteric extension, periprosthetic fractures, and pathological fractures associated with primary or metastatic bone tumors and miscellaneous bone diseases (eg, Paget’s disease, fibrous dysplasia). Narcolepsy due to swine influenza A (H1N1) vaccination (Pandemrix) [ 21 ] (1) Onset of symptoms after Pandemrix vaccination. Narolepsy type 1: (1) The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months; (2) The presence of one or both of the following (a-b): (a) Cataplexy and a mean sleep latency of ≤8 min and two or more sleep onset REM periods (SOREMPs) on a multiple sleep latency test (MSLT) performed according to standard techniques.…”

Moving from Empirical to Rational Vaccine Design in the ‘Omics’ Era

“…Immunological characterization of patients with viscerotropic disease showed 200-fold elevated levels of CD14+CD16+ inflammatory monocytes [28]. Genetic background studies of narcoleptic patients showed association of symptoms with ethnic background including the HLA-DQB1*06:02 genotype [29]. These examples show that it is possible to identify clinical and genetic markers that may lead to adverse reaction to a specific vaccine.…”