Cluster headache (CH) is a primary headache disorder with a complex genetic background. Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The HFE gene encodes for a protein involved in iron metabolism, while genetic variants in HFE have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common HFE H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the HFE rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (p > 0.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the HFE gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that HFE H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in HFE gene may be potentially regarded as a disease modifier genetic factor in CH.

丛集性头痛 (CH) 是一种具有复杂遗传背景的原发性头痛疾病。几项研究表明铁稳态与原发性头痛的病理生理学之间存在潜在联系。的HFE的蛋白质的基因编码参与铁代谢，而在遗传变异体HFE已经用遗传性血色病（HH），铁过载紊乱相关联。本研究的目的是检查更常见的HFE H63D 变异与东南欧高加索 (SEC) 血统人群中发生 CH 和不同临床表型的易感性之间的关联。对来自 128 名 CH 患者和 294 名神经系统健康对照的基因组 DNA 样本进行了HFE基因分型rs1799945 (H63D) 变体。H63D 基因型和等位基因频率分布在患者和对照之间没有显着差异（p  > 0.05）。亚组分析显示，与偶发性 CH 患者相比，慢性期变异 G 等位基因的出现频率明显更高，这表明HFE基因可能与疾病慢性化的易感性有关。尽管在 CH 队列中不太流行的 H63D 变异 G 等位基因的纯合度很小，但本研究的结果与先前在 CH 和偏头痛患者中的研究一致，表明HFEH63D 变体改变了疾病的临床特征。因此，尽管在当前的 SEC 队列中不存在本身与 CH 易感性的关联，但HFE基因的变异性可能被视为 CH 的疾病修饰遗传因素。