HLA-DQ Sequencing Studies in Narcolepsy/Hypocretin Deficiency

描述(申请人提供)：发作性睡病-猝倒影响0.05%的美国人口。这种疾病的原因是下丘脑中的下丘脑中的下丘脑/增食欲素神经元的丢失，可能是自身免疫性的原因。这种疾病唯一与人类白细胞抗原(人类白细胞抗原)DQB1*0602密切相关，并可能成为研究其他影响大脑的自身免疫性疾病的模型。与T细胞受体(TCR)基因座的相关性也较弱。本研究的重点是对4,000名正常人和3,500名DQB1*0602类单倍型患者的人类白细胞抗原-DQA1和DQB1外显子及启动子区域进行测序。患者和对照组将包括亚洲人、高加索人和非裔美国人。该项目的最终目标是确定哪些DQA1和DQB1氨基酸与疾病易感性有关，并对所涉及的DQ异源二聚体结合位点进行建模。与TCR领域正在进行的工作一起，该项目提供了对涉及发作性睡病易感性的人类白细胞抗原-多肽-TCR三分子复合体进行建模的机会。它还将利用最新开发的Flx 454钛测序技术来生成和分析高通量、低成本的全人类白细胞抗原DQA1和DQB1序列，并开发和完善新的统计分析工具，如序列变异类型分析(SFVT)，用于疾病相关性研究。 公共卫生相关性(由申请人提供)：发作性睡病影响2000美国人中的1/2000，是一种常见的神经疾病。这项拟议的研究可能会为这种疾病带来新的治疗途径。

DESCRIPTION (provided by applicant): Narcolepsy-cataplexy affects 0.05% of the US population. The cause of the disorder is a loss of hypocretin/orexin neurons in the hypothalamus, of likely autoimmune origin. The disease is uniquely tightly associated with Human Leukocyte Antigen (HLA) DQB1*0602, and may serve as a model to the study of other autoimmune diseases affecting the brain. A weaker association with the T-Cell receptor (TCR) loci is also found. The focus of this application is to sequence the HLA-DQA1 and DQB1 exons and promoter region in 4,000 controls and 3,500 patients with DQB1*0602 like haplotypes. Patients and controls will include Asians, Caucasians and African Americans. The ultimate goal of this project is to determine which DQA1 and DQB1 amino acids are involved in disease susceptibility, and to model the DQ heterodimer binding site involved. Together with work ongoing in the TCR arena, this project offers the opportunity to model the HLA-peptide-TCR trimolecular complex involved in narcolepsy susceptibility. It will also make use of the newly developed FLX 454 titanium sequencing technique to generate and analyze high throughput, low cost full HLA DQA1 and DQB1 sequence, and to develop and perfect new statistical analytic tools, such as the Sequence Variant Type Analysis (SFVT), for disease association studies. PUBLIC HEALTH RELEVANCE (provided by applicant): Narcolepsy affects 1/2000 Americans and is a common neurological disorder. The proposed study may lead to new therapeutic avenues for the disorder.