Variant between CPT1B and CHKB associated with susceptibility to narcolepsy
Variant between CPT1B and CHKB associated with susceptibility to narcolepsy
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DOI：
10.1038/ng.231
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发表时间：
2008-11-01
期刊：
影响因子：
30.8
通讯作者：
Tokunaga, Katsushi
中科院分区：
文献类型：
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作者：
Miyagawa, Taku;Kawashima, Minae;Tokunaga, Katsushi
发作性睡病是一种以嗜睡、猝倒和快速眼动(REM)睡眠异常为特征的睡眠障碍，与人类白细胞抗原DRB1*1501(M17378)和人类白细胞抗原DQB1*0602(M20432)密切相关。人类白细胞抗原区域以外的易感基因也可能参与其中。我们使用500K SNP微阵列在222名日本发作性睡病患者和389名日本对照人群中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名日本对照人群中复制了最热门的结果，随后对424名韩国人、785名欧洲人后裔和184名非裔美国人进行了测试。位于CPT1B和CHKB之间的一个SNP rs5770917与日本人发作性睡病相关(rs5770917[C]，优势比(OR)=1.79，合并后P=4.4×10(-7))及其他祖先组(OR=1.40，P=0.02)。实时定量聚合酶链式反应分析显示，携带C等位基因的受试者中CPT1B和CHKB的表达降低，这表明调节CPT1B或CHKB表达的基因变异与发作性睡病有关。这两个基因中的任何一个都是一个合理的候选基因，因为CPT1B调节贝塔氧化，这是一种参与调节REM睡眠期间theta频率的途径，而CHKB是一种参与胆碱代谢的酶，胆碱是REM和清醒调节神经递质乙酰胆碱的前体。
Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (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.