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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
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]