DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe

作者：Tafti Mehdi^*; Hor Hyun; Dauvilliers Yves; Lammers Gert J; Overeem Sebastiaan; Mayer Geert; Javidi Sirous; Iranzo Alex; Santamaria Joan; Peraita Adrados Rosa; Vicario Jose 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 Raphael; Haba Rubio Jose; Feketeova Eva; Hogl Birgit

来源：SLEEP, 2014, 37(1): 19-U228.

DOI：10.5665/sleep.3300

• Autoimmunity
• GWAS
• H1N1 vaccination
• genetics

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. %26lt;br%26gt;Design: Retrospective case-control study. %26lt;br%26gt;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 %26lt; 10-4 mapping to DHSs. Ten SNPs tagging these sites, HLA-DQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. %26lt;br%26gt;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. %26lt;br%26gt;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 %26lt; 2x10-9) and rs1154155 within the TRA locus (P %26lt; 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. %26lt;br%26gt;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.

• 出版日期2014-1-1