Dataset Information

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

ABSTRACT: STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

SUBMITTER: Tafti M

PROVIDER: S-EPMC3865351 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

Tafti Mehdi M Hor Hyun H Dauvilliers Yves Y Lammers Gert J GJ Overeem Sebastiaan S Mayer Geert G Javidi Sirous S Iranzo Alex A Santamaria Joan J Peraita-Adrados Rosa R Vicario José L JL Arnulf Isabelle I Plazzi Giuseppe G Bayard Sophie S Poli Francesca F Pizza Fabio F Geisler Peter P Wierzbicka Aleksandra A Bassetti Claudio L CL Mathis Johannes J Lecendreux Michel M Donjacour Claire E H M CE van der Heide Astrid A Heinzer Raphaël R Haba-Rubio José J Feketeova Eva E Högl Birgit B Frauscher Birgit B Benetó Antonio A Khatami Ramin R Cañellas Francesca F Pfister Corinne C Scholz Sabine S Billiard Michel M Baumann Christian R CR Ercilla Guadalupe G Verduijn Willem W Claas Frans H J FH Dubois Valérie V Nowak Jacek J Eberhard Hans-Peter HP Pradervand Sylvain S Hor Charlotte N CN Testi Manuela M Tiercy Jean-Marie JM Kutalik Zoltán Z

Sleep 20140101 1

<h4>Study objective</h4>Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.<h4>Design</h4>Retrospective case-control study.<h4>Setting</h4>A recent study showed that over 76% of significant genome-wide association variants l ...[more]

PMID: 24381371

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Project description:To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (? 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1.University-based sleep clinics and laboratories.Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1.Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis.The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (? 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (? 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status.Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy.

Dataset Information

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

Publications

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

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