Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Nature Genetics (Impact Factor: 29.35). 09/2010; 42(9):786-9. DOI: 10.1038/ng.647
Source: PubMed


Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

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    • "The pathogenesis of sporadic narcolepsy with cataplexy is likely autoimmune with hypocretin neurons being a target (Kornum et al., 2011a), and possibly interacting with other neurotransmission systems during development (Sundvik et al., 2011). Narcolepsy with cataplexy is strongly associated with HLA– DQB1*06:02 (Mignot et al., 1994), an effect also modulated by the presence of other HLA subtypes (Mignot et al., 2001; Hor et al., 2010), and by polymorphisms in the T cell receptor alpha (Hallmayer et al., 2009; Hor et al., 2010), P2YR11 receptor and other loci (Kornum et al., 2011b; Faraco et al., 2013). Clinical and biochemical evidence temporally links the onset of narcolepsy with cataplexy symptoms with an activation of the immune system by infection, either bacterial such as streptococcal (Aran et al., 2009), or viral such as H1N1 flu or vaccination (Han et al., 2011; Partinen et al., 2012), or with an autoimmune response proved by production of self-targeted antibodies (Cvetkovic-Lopes et al., 2010; Kawashima et al., 2010). "
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    ABSTRACT: Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e. brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels.
    Full-text · Article · Oct 2013 · Brain
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    • "Idiopathic narcolepsy with cataplexy (NC), like multiple sclerosis (MS), is considered to be an autoimmune disorder leading to a selective loss of hypothalamic hypocretin neurons [1]. The main arguments of an autoimmune cause include the strong association with HLA-DQB1⁄06:02, a strong protective effect of DRB1⁄13:01- DQB1⁄06:03 haplotype [2], a recent discovery of circulating TRIB2-specific antibodies reactive to hypocretin neurons [3], and a genome-wide association with a T-cell receptor a chain [4]. "

    Full-text · Article · May 2013 · Sleep Medicine
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    • "The data were derived from a number of research projects, some published (e.g. Dauvilliers et al., 2001; Hor et al., 2010). Local ethics committees approved the recruitment of patients for research protocols, and all patients gave their consent to participate. "
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    ABSTRACT: The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.
    Full-text · Article · Mar 2013 · Journal of Sleep Research
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