DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.
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Tafti Mehdi, Hor Hyun, Dauvilliers Yves, Lammers Gert J, Overeem Sebastiaan, Mayer Geert, Javidi Sirous, Iranzo Alex, Santamaria Joan, Peraita-Adrados Rosa, Vicario José L, Arnulf Isabelle, Plazzi Giuseppe, Bayard Sophie, Poli Francesca, Pizza Fabio, Geisler Peter, Wierzbicka Aleksandra, Bassetti Claudio L, Mathis Johannes, Lecendreux Michel, Donjacour Claire E H M, van der Heide Astrid, Heinzer Raphaël, Haba-Rubio José, Feketeova Eva, Högl Birgit, Frauscher Birgit, Benetó Antonio, Khatami Ramin, Cañellas Francesca, Pfister Corinne, Scholz Sabine, Billiard Michel, Baumann Christian R, Ercilla Guadalupe, Verduijn Willem, Claas Frans H J, Dubois Valérie, Nowak Jacek, Eberhard Hans-Peter, Pradervand Sylvain, Hor Charlotte N, Testi Manuela, Tiercy Jean-Marie, Kutalik Zoltán
Аннотация
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.