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

Academic Article
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Overview

authors

  • Hallmayer, J.
  • Faraco, J.
  • Lin, L.
  • Hesselson, S.
  • Winkelmann, J.
  • Kawashima, M.
  • Mayer, G.
  • Plazzi, G.
  • Nevsimalova, S.
  • Bourgin, P.
  • Hong, S. S. C.
  • Honda, Y.
  • Honda, M.
  • Hogl, B.
  • Longstreth, W. T.
  • Montplaisir, J.
  • Kemlink, D.
  • Einen, M.
  • Chen, J.
  • Musone, S. L.
  • Akana, M.
  • Miyagawa, T.
  • Duan, J.
  • Desautels, A.
  • Erhardt, C.
  • Hesla, P. E.
  • Poli, F.
  • Frauscher, B.
  • Jeong, J. H.
  • Lee, S. P.
  • Ton, T. G. N.
  • Kvale, M.
  • Kolesar, L.
  • Dobrovolna, M.
  • Nepom, G. T.
  • Salomon, Daniel
  • Wichmann, H. E.
  • Rouleau, G. A.
  • Gieger, C.
  • Levinson, D. F.
  • Gejman, P. V.
  • Meitinger, T.
  • Young, T.
  • Peppard, P.
  • Tokunaga, K.
  • Kwok, P. Y.
  • Risch, N.
  • Mignot, E.

publication date

  • 2009

journal

  • Nature Genetics  Journal

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.

subject areas

  • Animals
  • Chromosomes, Human, Pair 14
  • Chromosomes, Human, Pair 22
  • DNA Replication
  • Dogs
  • Genotype
  • Humans
  • Hypothalamus
  • Mice
  • Narcolepsy
  • Polymorphism, Single Nucleotide
  • Receptors, Antigen, T-Cell, alpha-beta
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Identity

PubMed Central ID

  • PMC2803042

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/ng.372

PubMed ID

  • 19412176
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Additional Document Info

start page

  • 708

end page

  • 711

volume

  • 41

issue

  • 6

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