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

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Abstract
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 individuals1,2. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported7,8. 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 disorders9; 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 disorders9.