Mehdi Tafti1,2, Gert J Lammers3,4, Yves Dauvilliers5,6, Sebastiaan Overeem7, Geert Mayer8, Jacek Nowak9, Corinne Pfister1, Valérie Dubois10, Jean-François Eliaou11, Hans-Peter Eberhard12, Roland Liblau13, Aleksandra Wierzbicka14, Peter Geisler15, Claudio L Bassetti16, Johannes Mathis16, Michel Lecendreux17, Ramin Khatami18, Raphaël Heinzer2, José Haba-Rubio2, Eva Feketeova19, Christian R Baumann20, Zoltán Kutalik21,22, Jean-Marie Tiercy23. 1. Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland. 2. Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. 3. Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands. 4. Sleep-Wake Center of the Stichting Epilepsie Instellingen Netherland, Heemstede, the Netherlands. 5. INSERM-1061, Montpellier, France. 6. National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Neurology, Gui-de-Chauliac Hospital, Montpellier, France. 7. Sleep Medicine Center 'Kempenhaeghe', Heeze, the Netherlands. 8. Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany. 9. Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. 10. HLA Laboratory, Etablissement Français du Sang, Lyon, France. 11. Department of Immunology, CHRU of Montpellier, University of Montpellier, France. 12. German National Bone Marrow Donor Registry, Ulm, Germany. 13. INSERM-UMR1043, CNRS-U5282, Université de Toulouse, Centre de Physiopathologie Toulouse Purpan (CPTP), Toulouse, France. 14. Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland. 15. Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany. 16. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerland. 17. 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. 18. Sleep Medicine, Barmelweid Clinic, Switzerland. 19. Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia. 20. Department of Neurology, University Hospital Zurich, Switzerland. 21. Swiss Institute of Bioinformatics, Lausanne, Switzerland. 22. Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland. 23. National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland.
Abstract
STUDY OBJECTIVES: 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.
STUDY OBJECTIVES: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.
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