Journal Article

Narcolepsy is strongly associated with the T-cell receptor alpha locus

Ton, Thanh G N, Duan, Jubao, Honda, Makoto, Kvale, Mark, Poli, Francesca, Frauscher, Birgit, Montplaisir, Jacques, Meitinger, Thomas, Winkelmann, Juliane, Honda, Yutaka, Mayer, Geert, Einen, Mali, Dobrovolná, Marie, Lee, Sung-Pil, Erhardt, Christine, Kolesar, Libor, Kawashima, Minae, Kemlink, David, Gieger, Christian, Longstreth, William T, Chen, Justin, Peppard, Paul, Bourgin, Patrice, Hallmayer, Joachim, Gejman, Pablo V, Young, Terry, Miyagawa, Taku, Plazzi, Giuseppe, Hesselson, Stephanie, Akana, Matthew, Lin, Ling, Tokunaga, Katsushi, Salomon, Dan, Nevsimalova, Sona, Hong, Seung-Chul, Musone, Stacy L, Högl, Birgit, Desautels, Alex, Kwok, Pui-Yan, Rouleau, Guy A, Risch, Neil, Jeong, Jong-Hyun, Nepom, Gerald T, Faraco, Juliette, Wichmann, H-Erich, Levinson, Douglas F, Mignot, Emmanuel, Hesla, Per Egil

2009

Overview

Emmanuel Mignot and colleagues report that variants in the T-cell receptor alpha ( TRA@ ) locus are strongly associated with narcolepsy. This is the first documented involvement of the TCR locus in human disease and will shed light on how HLA-TCR interactions contribute to organ-specific autoimmune targeting. Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals 1 , 2 . Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3 ) and later sublocalized to DQB1 * 0602 (ref. 4 ). Following studies in dogs 5 and mice 6 , a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported 7 , 8 . Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10 −21 , 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders 9 ; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders 9 .

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: African Americans / Agriculture / Animal Genetics and Genomics / Animals / Antigen receptors, T cell / Asian people / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromosomes, Human, Pair 14 - genetics / Chromosomes, Human, Pair 22 - genetics / Data analysis / Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes / DNA Replication - genetics / Dogs / Fundamental and applied biological sciences. Psychology / Gene Function / Gene loci / Genetic aspects / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genotype / Histocompatibility antigens / HLA histocompatibility antigens / Human Genetics / Humans / Hypothalamus - immunology / Hypothalamus - pathology / Independent sample / letter / Medical research / Medical sciences / Mice / Minority & ethnic groups / Narcolepsy / Narcolepsy - genetics / Narcolepsy - immunology / Nervous system (semeiology, syndromes) / Neurological disorders / Neurology / Neurons / Physiological aspects / Polymorphism, Single Nucleotide / Receptors / Receptors, Antigen, T-Cell, alpha-beta - genetics / Risk factors / Sample size / Sleep disorders / Software packages / T cells