DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe - PubMed (original) (raw)

. 2014 Jan 1;37(1):19-25.

doi: 10.5665/sleep.3300.

Hyun Hor 2, Yves Dauvilliers 3, Gert J Lammers 4, Sebastiaan Overeem 5, Geert Mayer 6, Sirous Javidi 6, Alex Iranzo 7, Joan Santamaria 7, Rosa Peraita-Adrados 8, José L Vicario 9, Isabelle Arnulf 10, Giuseppe Plazzi 11, Sophie Bayard 3, Francesca Poli 11, Fabio Pizza 11, Peter Geisler 12, Aleksandra Wierzbicka 13, Claudio L Bassetti 14, Johannes Mathis 14, Michel Lecendreux 15, Claire E H M Donjacour 16, Astrid van der Heide 16, Raphaël Heinzer 17, José Haba-Rubio 17, Eva Feketeova 18, Birgit Högl 19, Birgit Frauscher 19, Antonio Benetó 20, Ramin Khatami 21, Francesca Cañellas 22, Corinne Pfister 23, Sabine Scholz 24, Michel Billiard 24, Christian R Baumann 25, Guadalupe Ercilla 26, Willem Verduijn 27, Frans H J Claas 27, Valérie Dubois 28, Jacek Nowak 29, Hans-Peter Eberhard 30, Sylvain Pradervand 31, Charlotte N Hor 32, Manuela Testi 33, Jean-Marie Tiercy 34, Zoltán Kutalik 35

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

Mehdi Tafti et al. Sleep. 2014.

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.

Keywords: Autoimmunity; GWAS; H1N1 vaccination; genetics.

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