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Erratum in

  • Nat Genet. 2009 Jul;41(7):859. Hong, Sheng Seung-Chul [corrected to Hong, Seung-Chul]

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.

Figures

Figure 1
Figure 1
Schematic representation of the TCRA locus and of SNPs associated with narcolepsy. The TCRA locus consists of clusters of V and J segments and exons of the C region. The T-Cell Receptor delta locus (TRD) resides within the TCRA locus. A 40kb region of LD encompasses half of the TRAJ segments and is flanked by TRAJ32 and the second exon of the TRAC gene. Within this region, 3 SNPs are highly associated with narcolepsy, separated by 3 and 15 kb successively. In Caucasians, the association is equivalent with rs12587781 and rs1154155 (Tables 1 and 2), and LD is extremely high (r2=0.97 and 0,94 n=1154 cases, n=1425 controls, correlations calculated using Haploview). In contrast, the association is stronger with rs1154155 than rs12587781 in Asians (Table 2), a phenomenon explained by the lower LD in this ethnic group (r2=0.62 and 0.52, n=553 cases, n=603 controls). Intermediate LD was seen in African-American individuals (r2=0.74 and 0.71, n=124 cases, n=142 controls). The association with rs1263646 is weaker across all ethnic groups, most notably Asians and African Americans (Table 2). These results, depicted as values for cases and controls combined in this figure, illustrate the value of trans-ethnic mapping.

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