title: HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.
abstract: Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Ollila
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Ravel
authors.affiliation: Department of Pulmonary Medicine, Peking University People's Hospital, 100044 Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Juliette
authors.initials: J
authors.lastname: Faraco
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, University of Washington, PO box 357232, Seattle, WA 98195, USA.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
authors.affiliation: INSERM U1061, Reference Center for Narcolepsy, Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, Centre Hospitalier Régional Universitaire Montpellier, 34090 Montpellier, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy; IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.affiliation: Department of Psychiatry, St. Vincent's Hospital, The Catholic University of Korea, 442-723 Suwon, Korea.
authors.forename: Seung-Chul
authors.initials: SC
authors.lastname: Hong
authors.affiliation: Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Jennum
authors.affiliation: Norwegian Resource Center for ADHD, TS, and Narcolepsy, Oslo University Hospital, 0450 Ullevål, Norway.
authors.forename: Stine
authors.initials: S
authors.lastname: Knudsen
authors.affiliation: Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark; Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, 2600 Glostrup, Denmark.
authors.forename: Birgitte R
authors.initials: BR
authors.lastname: Kornum
authors.affiliation: Department of Pulmonary Medicine, Peking University People's Hospital, 100044 Beijing, China.
authors.forename: Xiao Song
authors.initials: XS
authors.lastname: Dong
authors.affiliation: Department of Pulmonary Medicine, Peking University People's Hospital, 100044 Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Heeseung
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.
authors.forename: Cristin
authors.initials: C
authors.lastname: Coquillard
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Mahlios
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Otto
authors.initials: O
authors.lastname: Jolanki
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
authors.forename: Mali
authors.initials: M
authors.lastname: Einen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.affiliation: Centre National de Réferénce Narcolepsie et Hypersomnie, 75019 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavault
authors.affiliation: Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Högl
authors.affiliation: Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Frauscher
authors.affiliation: Mater Private Hospital, Dublin 7, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Crowe
authors.affiliation: Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, 00100 Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Partinen
authors.affiliation: Chang Gung Memorial Hospital and University, Taipei 10591, Taiwan.
authors.forename: Yu Shu
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University, 67084 Strasbourg, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bourgin
authors.affiliation: Institute of Clinical Medicine, University of Helsinki, 00100 Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.affiliation: Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Désautels
authors.affiliation: Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Psychiatry, University of Montreal, Montreal QC H3T 1J4, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Montplaisir
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609-1673, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Mack
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mindrinos
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez-Vina
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA. Electronic address: mignot@stanford.edu.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism; D006682:HLA-DP Antigens / Q000235:genetics / Q000378:metabolism; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000378:metabolism; D059848:HLA-DQ alpha-Chains / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics; D008297:Male; D009290:Narcolepsy / Q000235:genetics*; D012307:Risk Factors; D044465:White People
chemical_list: D015235:HLA-B Antigens; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I