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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-06

AUTHORS

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

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. More... »

PAGES

708-711

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.372

DOI

http://dx.doi.org/10.1038/ng.372

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008025259

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19412176


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43 schema:description 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.
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