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Narcolepsy is strongly associated with the T-cell receptor alpha locus.
Nat. Genet. 41, 708-711 (2009)
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter genome-wide association; information; evolution; mutation; region; gene
ISSN (print) / ISBN 1061-4036
Zeitschrift Nature Genetics
Quellenangaben Band: 41, Heft: 6, Seiten: 708-711
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed