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- Title
Narcolepsy is strongly associated with the T-cell receptor alpha locus.
- Authors
Hallmayer, Joachim; Faraco, Juliette; Ling Lin; Hesselson, Stephanie; Winkelmann, Juliane; Kawashima, Minae; Mayer, Geert; Plazzi, Giuseppe; Nevsimalova, Sona; Bourgin, Patrice; Sheng Seung-Chul Hong; Honda, Yutaka; Honda, Makoto; Högl, Birgit; Longstreth, William T.; Montplaisir, Jacques; Kemlink, David; Einen, Mali; Chen, Justin; Musone, Stacy L.
- Abstract
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. 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 and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. 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; 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.
- Subjects
NARCOLEPSY; T cell receptors; DROWSINESS; OREXINS; CAUCASIAN race; GENOMES; PEPTIDES
- Publication
Nature Genetics, 2009, Vol 41, Issue 6, p708
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.372