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.

• Authors: Mehdi Tafti, Hyun Hor, Yves Dauvilliers, Gert J Lammers, Sebastiaan Overeem, Geert Mayer, Sirous Javidi, Alex Iranzo, Joan Santamaria, Rosa Peraita-Adrados, José L Vicario, Isabelle Arnulf, Giuseppe Plazzi, Sophie Bayard, Francesca Poli, Fabio Pizza, Peter Geisler, Aleksandra Wierzbicka, Claudio L Bassetti, Johannes Mathis, Michel Lecendreux, Claire E H M Donjacour, Astrid van der Heide, Raphaël Heinzer, José Haba-Rubio, Eva Feketeova, Birgit Högl, Birgit Frauscher, Antonio Benetó, Ramin Khatami, Francesca Cañellas, Corinne Pfister, Sabine Scholz, Michel Billiard, Christian R Baumann, Guadalupe Ercilla, Willem Verduijn, Frans H J Claas, Valérie Dubois, Jacek Nowak, Hans-Peter Eberhard, Sylvain Pradervand, Charlotte N Hor, Manuela Testi, Jean-Marie Tiercy, Zoltán Kutalik
• Journal: Sleep (Sleep) Vol. 37 Issue 1 Pg. 19-25 (Jan 01 2014) ISSN: 1550-9109 [Electronic] United States
• PMID: 24381371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-DQ beta-Chains
• HLA-DQB1 antigen
• Influenza Vaccines
• Deoxyribonuclease I

Topics

• Alleles
• Cataplexy (genetics)
• Deoxyribonuclease I (metabolism)
• Europe (epidemiology, ethnology)
• Exome (genetics)
• Genetic Predisposition to Disease (genetics)
• Genome-Wide Association Study
• HLA-DQ beta-Chains (genetics)
• Humans
• Influenza A Virus, H1N1 Subtype (immunology)
• Influenza Vaccines (administration & dosage)
• Narcolepsy (genetics)
• Odds Ratio
• Polymorphism, Single Nucleotide (genetics)
• Retrospective Studies
• Vaccination
• White People (genetics)