ImmunoChip study implicates antigen presentation to T cells in narcolepsy

• Published in: PLoS genetics 2013-02, Vol.9 (2), p.e1003270-e1003270
• Main Authors: Faraco, Juliette, Lin, Ling, Kornum, Birgitte Rahbek, Kenny, Eimear E, Trynka, Gosia, Einen, Mali, Rico, Tom J, Lichtner, Peter, Dauvilliers, Yves, Arnulf, Isabelle, Lecendreux, Michel, Javidi, Sirous, Geisler, Peter, Mayer, Geert, Pizza, Fabio, Poli, Francesca, Plazzi, Giuseppe, Overeem, Sebastiaan, Lammers, Gert Jan, Kemlink, David, Sonka, Karel, Nevsimalova, Sona, Rouleau, Guy, Desautels, Alex, Montplaisir, Jacques, Frauscher, Birgit, Ehrmann, Laura, Högl, Birgit, Jennum, Poul, Bourgin, Patrice, Peraita-Adrados, Rosa, Iranzo, Alex, Bassetti, Claudio, Chen, Wei-Min, Concannon, Patrick, Thompson, Susan D, Damotte, Vincent, Fontaine, Bertrand, Breban, Maxime, Gieger, Christian, Klopp, Norman, Deloukas, Panos, Wijmenga, Cisca, Hallmayer, Joachim, Onengut-Gumuscu, Suna, Rich, Stephen S, Winkelmann, Juliane, Mignot, Emmanuel
• Format: Article
• Language: English
• Subjects: Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - metabolism; Biology; Confidence intervals; Disease; Disease susceptibility; European Continental Ancestry Group; Gene expression; Genealogy; Genetic aspects; Genetic Association Studies; Genetics; Genomes; Grants; Haplotypes; Health aspects; Health sciences; HLA Antigens - genetics; HLA Antigens - immunology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Lymphocytes; Narcolepsy; Narcolepsy - genetics; Narcolepsy - immunology; Narcolepsy - physiopathology; Neuropeptides - genetics; Neuropeptides - immunology; Neuropeptides - metabolism; Orexins; Physiological aspects; Principal components analysis; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Sleep disorders; T cell receptors; T cells
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003270

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.