Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.
Headache. 2019 Mar;59(3):410-417. doi: 10.1111/head.13462. Epub 2019 Jan 16.
The purpose of this study was to investigate the HCRTR2 gene variants rs3122156, rs2653342, and rs2653349 in a large homogenous Swedish case-control cohort in order to further evaluate the possible contribution of HCRTR2 to cluster headache.
Cluster headache is a severe neurovascular disorder and the pathophysiology is not yet fully understood. Due to striking circadian and circannual patterns of this disease, the hypothalamus has been a research focus in cluster headache. Several studies with many different cohorts from Europe have investigated the hypocretin receptor 2 (HCRTR2) gene, which is expressed in the hypothalamus. In particular, one HCRTR2 single nucleotide polymorphism, rs2653349, has been subject to a number of genetic association studies on cluster headache, with conflicting results. Two other HCRTR2 gene variants, rs2653342 and rs2653349, have been reported to be linked to cluster headache in an Italian study.
We genotyped a total of 517 patients diagnosed with cluster headache and 581 controls, representing a general Swedish population, for rs3122156, rs2653342, and rs2653349 using quantitative real-time PCR. Statistical analyses of genotype, allele, and haplotype frequencies for the 3 gene variants were performed comparing patients and controls.
For rs3122156, the minor allele frequency in patients was 25.9% compared to 29.9% in controls (P = .0421). However, this significance did not hold after correction for multiple testing. The minor allele frequencies for rs2653342 (14.7% vs 14.7%) and rs2653349 (19.5% vs 18.8%) were similar for patients and controls. Furthermore, we found one haplotype that was significantly less common in patients than controls (P = .0264). This haplotype included the minor allele for rs3122156 and the major alleles for rs2653342 and rs2653349. Significance did not hold after applying a permutation test.
Our data show a trend for association between cluster headache and the HCRTR2 polymorphism rs3122156, where the minor allele seems to be a protective factor. However, the other 2 HCRTR2 gene variants, including the previously reported rs2653349, were not associated with cluster headache in our Swedish material. A comparison with previous studies points to variance in genotype and allele frequencies among the different populations, which most likely contributes to the opposing results regarding rs2653349. Although the results from this study do not strongly support an association, HCRTR2 remains an interesting candidate gene for involvement in the pathophysiology of cluster headache.
本研究旨在对大量瑞典同质病例对照队列中的 HCRTR2 基因变体 rs3122156、rs2653342 和 rs2653349 进行研究，以进一步评估 HCRTR2 对丛集性头痛的可能贡献。
丛集性头痛是一种严重的神经血管疾病，其病理生理学尚未完全阐明。由于这种疾病具有明显的昼夜和年周期模式，下丘脑一直是丛集性头痛的研究焦点。来自欧洲的多项不同队列的多项研究已经研究了下丘脑分泌素受体 2 (HCRTR2) 基因，该基因在下丘脑表达。特别是，HCRTR2 基因的一个单核苷酸多态性 rs2653349 已经在多项丛集性头痛的遗传关联研究中进行了研究，但结果存在冲突。另外两个 HCRTR2 基因变体 rs2653342 和 rs2653349 曾被报道与意大利的丛集性头痛有关。
我们使用实时定量 PCR 对 517 名确诊为丛集性头痛的患者和 581 名代表一般瑞典人群的对照者进行了 rs3122156、rs2653342 和 rs2653349 的基因分型。比较了患者和对照组中这 3 个基因变体的基因型、等位基因和单倍型频率的统计分析。
与对照组相比，rs3122156 的次要等位基因频率在患者中为 25.9%，而在对照组中为 29.9%（P =.0421）。然而，在经过多次检验校正后，这种显著性并不成立。rs2653342（14.7%比 14.7%）和 rs2653349（19.5%比 18.8%）的次要等位基因频率在患者和对照组之间相似。此外，我们发现一个单倍型在患者中明显比对照组少见（P =.0264）。该单倍型包括 rs3122156 的次要等位基因和 rs2653342 和 rs2653349 的主要等位基因。应用置换检验后，该结果不具有显著性。
我们的数据显示，丛集性头痛与 HCRTR2 多态性 rs3122156 之间存在关联趋势，其中次要等位基因似乎是一种保护因素。然而，我们的瑞典材料中包括之前报道的 rs2653349 在内的其他 2 个 HCRTR2 基因变体与丛集性头痛无关。与以往研究的比较表明，不同人群的基因型和等位基因频率存在差异，这很可能导致 rs2653349 的结果存在差异。尽管这项研究的结果并没有强烈支持相关性，但 HCRTR2 仍然是参与丛集性头痛病理生理学的一个有趣候选基因。
