A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia
A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia
复制标题
9q34.11 处的变异与 HLA-DQB1*06:02 相关
DOI：
10.1038/s10038-018-0518-8
复制
发表时间：
2018
期刊：
影响因子：
3.5
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Miyagawa T;Khor SS;Toyoda H;Kanbayashi T;Imanishi A;Sagawa Y;Kotorii N;Kotorii T;Ariyoshi Y;Hashizume Y;Ogi K;Hiejima H;Kamei Y;Hida A;et al.
原发性嗜睡症（EHS）是一种终身性疾病，其特征是白天过度嗜睡而无症状。EHS与人类白细胞抗原（HLA）-DQB 1 *06：02相关，类似于发作性睡病伴癫痫发作（发作性睡病）。以往的研究表明，DQB 1 *06：02阳性和阴性EHS的临床特征不同，遵循不同的病理途径，DQB 1 *06：02阳性EHS与发作性睡病具有相同的易感基因。在本研究中，我们报告了一项DQB 1 *06：02阴性EHS（408例患者和2247例健康对照，均为日本人）复制的全基因组关联研究。一个单核苷酸多态性rs 10988217位于肉毒碱O-乙酰转移酶（CRAT）上游15 kb处，与DQB 1 *06：02阴性EHS显著相关（P= 7.5 × 10−9，比值比= 2.63）。疾病相关SNP的风险等位基因与包括脑组织在内的各种组织和细胞类型中CRAs的高表达水平相关。此外，该风险等位基因与人体血液中琥珀酰肉毒碱水平（P= 1.4 × 10−18）相关。该区域的主要SNP与DQB 1 *06：02阴性EHS和琥珀酰肉碱水平的相关性相同。结果表明，DQB 1 *06：02阴性的EHS可能与能量代谢途径的潜在功能障碍有关。
Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest thatDQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways.DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication forDQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated withDQB1*06:02-negative EHS (P= 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels ofCRATin various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P= 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with bothDQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest thatDQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.