Miyagawa Taku, Kawashima Minae, Nishida Nao, Ohashi Jun, Kimura Ryosuke, Fujimoto Akihiro, Shimada Mihoko, Morishita Shinichi, Shigeta Takashi, Lin Ling, Hong Seung-Chul, Faraco Juliette, Shin Yoon-Kyung, Jeong Jong-Hyun, Okazaki Yuji, Tsuji Shoji, Honda Makoto, Honda Yutaka, Mignot Emmanuel, Tokunaga Katsushi
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Nat Genet. 2008 Nov;40(11):1324-8. doi: 10.1038/ng.231. Epub 2008 Sep 28.
Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB11501 (M17378) and HLA-DQB10602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 x 10(-7)) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.
发作性睡病（下丘脑分泌素缺乏症）是一种以嗜睡、猝倒和快速眼动（REM）睡眠异常为特征的睡眠障碍，与HLA - DRB11501（M17378）和HLA - DQB10602（M20432）密切相关。除HLA区域的基因外，其他易感基因也可能参与其中。我们使用500K SNP微阵列对222名日本发作性睡病患者和389名日本对照进行了全基因组关联研究，并在159名日本发作性睡病患者和190名日本对照中对显著结果进行了重复验证，随后对424名韩国人、785名欧洲裔个体和184名非裔美国人进行了检测。位于CPT1B和CHKB之间的SNP rs5770917与日本人群中的发作性睡病相关（rs5770917[C]，优势比（OR）= 1.79，合并P = 4.4×10⁻⁷），在其他种族群体中也有相关性（OR = 1.40，P = 0.02）。白细胞的实时定量PCR分析表明，携带C等位基因的受试者中CPT1B和CHKB表达降低，这表明调节CPT1B或CHKB表达的基因变异与发作性睡病相关。这两个基因中的任何一个都是合理的候选基因，因为CPT1B调节β-氧化，这是一条在REM睡眠期间调节θ频率的途径，而CHKB是一种参与胆碱代谢的酶，胆碱是调节REM睡眠和觉醒的神经递质乙酰胆碱的前体。
