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Titel:

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

Dokumenttyp:
Journal Article; Article
Autor(en):
Hallmayer, J; Faraco, J; Lin, L; Hesselson, S; Winkelmann, J; Kawashima, M; Mayer, G; Plazzi, G; Nevsimalova, S; Bourgin, P; Hong, SS; Honda, Y; Honda, M; Högl, B; Longstreth, WT; Montplaisir, J; Kemlink, D; Einen, M; Chen, J; Musone, SL; Akana, M; Miyagawa, T; Duan, J; Desautels, A; Erhardt, C; Hesla, PE; Poli, F; Frauscher, B; Jeong, JH; Lee, SP; Ton, TG; Kvale, M; Kolesar, L; Dobrovolná, M; Nepom, GT; Salomon, D; Wichmann, HE; Rouleau, GA; Gieger, C; Levinson, DF; Gejman, PV; Meitinger, T; Yo...     »
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.
Zeitschriftentitel:
Nat Genet
Jahr:
2009
Band / Volume:
41
Heft / Issue:
6
Seitenangaben Beitrag:
708-11
Sprache:
eng
Volltext / DOI:
doi:10.1038/ng.372
PubMed:
http://view.ncbi.nlm.nih.gov/pubmed/19412176
Print-ISSN:
1061-4036
TUM Einrichtung:
Institut für Humangenetik; Neurologische Klinik und Poliklinik
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