Narcolepsy is strongly associated with the T-cell receptor alpha locus
Narcolepsy is strongly associated with the T-cell receptor alpha locus
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DOI：
10.1038/ng.372
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发表时间：
2009-06-01
期刊：
影响因子：
30.8
通讯作者：
Mignot, Emmanuel
中科院分区：
文献类型：
--
作者：
Hallmayer, Joachim;Faraco, Juliette;Mignot, Emmanuel
发作性睡病伴猝倒，其特点是嗜睡和快速进入快速眼动睡眠，每 2,000 人中就有 1 人受到影响(1,2)。发作性睡病首先被证明与 HLA-DR2 紧密相关（参考文献 3），后来又亚定位于 DQB1*0602（参考文献 4）。对狗 (5) 和小鼠 (6) 进行的研究表明，发作性睡病个体死后下丘脑中产生下丘脑分泌素的细胞损失了 95% (7,8)。使用白种人的全基因组关联 (GWA) 并在三个种族中进行复制，我们发现发作性睡病与 TRA@（T 细胞受体 α）基因座的多态性之间存在关联，其中 rs1154155 处的显着性最高（平均等位基因比值比 1.69，基因型比值比 1.94 和 2.55，P < 10(-21), 1,830案例， 2,164 个控件）。这是在任何疾病中首次记录到 TRA@ 位点的遗传参与，该位点编码 HLA 肽呈递的主要受体。目前尚不清楚特定的 HLA 等位基因如何赋予 100 多种 HLA 相关疾病的易感性(9)；因此，嗜睡病将为 HLA-TCR 相互作用如何促进器官特异性自身免疫靶向提供新的见解，并可作为 100 多种其他 HLA 相关疾病的模型 (9)。
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(9).