1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
2 Department of Clinical Neuroscience, Division of Neurology, Karolinska University Hospital, Stockholm, Sweden.
Cephalalgia. 2018 Mar;38(3):496-502. doi: 10.1177/0333102417698709. Epub 2017 Mar 9.
Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.
背景 丛集性头痛的特征是反复发作的单侧剧烈头痛。大多数患者的主要特征之一是发作具有明显的节律性。CLOCK（Circadian Locomotor Output Cycles Kaput）基因编码一种转录因子，它是人类昼夜节律的基本驱动力，因此作为丛集性头痛的候选基因特别有趣。 方法 我们对一个大型瑞典丛集性头痛病例对照样本（449 例患者和 677 例对照）进行了关联研究，筛选了 CLOCK 基因中三个与昼夜节律偏好（rs1801260）或睡眠持续时间（rs11932595 和 rs12649507）相关的单核苷酸多态性（SNP）。我们还想研究鉴定出的相关 SNP 对 CLOCK 基因表达的影响。 结果 我们发现 rs12649507 与丛集性头痛显著相关（p=0.0069），当按发作报告的昼夜节律性进行分层时，这一数据得到了加强（p=0.0009）。我们在人原代成纤维细胞培养物中研究了 rs12649507 对 CLOCK 基因表达的影响，发现 CLOCK mRNA 表达显著增加（p=0.0232）。 结论 我们的结果加强了昼夜节律参与丛集性头痛的假设。
