title: Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity.
abstract: OBJECTIVE
  Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells.
  
  
  METHODS
  HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles.
  
  
  RESULTS
  HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10(-4)), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10(-3)), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10(-3)) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr(9) (OR = 1.32 [1.15-1.52] P = 6.95*10(-5)) and HLA-C-Ser(11) (OR = 1.34 [1.15-1.57] P = 2.43*10(-4)).
  
  
  CONCLUSIONS
  Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons.
authors.affiliation: Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland.|Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.|Sleep-Wake Center of the Stichting Epilepsie Instellingen Netherland, Heemstede, the Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Lammers
authors.affiliation: INSERM-1061, Montpellier, France.|National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.affiliation: Sleep Medicine Center 'Kempenhaeghe', Heeze, the Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Overeem
authors.affiliation: Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany.
authors.forename: Geert
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pfister
authors.affiliation: HLA Laboratory, Etablissement Français du Sang, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Department of Immunology, CHRU of Montpellier, University of Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Eliaou
authors.affiliation: German National Bone Marrow Donor Registry, Ulm, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Eberhard
authors.affiliation: INSERM-UMR1043, CNRS-U5282, Université de Toulouse, Centre de Physiopathologie Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.affiliation: Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wierzbicka
authors.affiliation: Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Geisler
authors.affiliation: Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerland.
authors.forename: Claudio L
authors.initials: CL
authors.lastname: Bassetti
authors.affiliation: Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Mathis
authors.affiliation: Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Child and Adolescent Psychopathology, Robert Debré Hospital, Paris VII University, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lecendreux
authors.affiliation: Sleep Medicine, Barmelweid Clinic, Switzerland.
authors.forename: Ramin
authors.initials: R
authors.lastname: Khatami
authors.affiliation: Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Heinzer
authors.affiliation: Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: José
authors.initials: J
authors.lastname: Haba-Rubio
authors.affiliation: Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia.
authors.forename: Eva
authors.initials: E
authors.lastname: Feketeova
authors.affiliation: Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Baumann
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tiercy
mesh_terms: D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002385:Cataplexy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000939:Epitopes / Q000276:immunology; D005060:Europe / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016017:Odds Ratio; D000068797:Orexins / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D000939:Epitopes; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D015395:Histocompatibility Antigens Class I; D000068797:Orexins
keywords: CD4; CD8; autoimmunity; cytotoxicity; hypocretin/orexin