Abstract
Cluster headache is a severe primary headache characterized by extremely painful attacks of unilateral headache. Verapamil is commonly used as a prophylactic treatment with good effect. In order to search for new pathways involved in the pathophysiology of cluster headache, we analyzed genetic variants that were previously linked to verapamil response in migraine in a Swedish cluster headache case-control sample. We used TaqMan qPCR for genetic screening and performed a gene expression analysis on associated genes in patient-derived fibroblasts, and further investigated which reference genes were suitable for analysis in fibroblasts from cluster headache patients. We discovered a significant association between anoctamin 3, a gene encoding a calcium-activated ion channel, and cluster headache. The association was not dependent on verapamil treatment since the associated variant, rs1531394, was also overrepresented in patients not using verapamil. No difference was found in the anoctamin 3 gene expression between controls and patients. Also, we determined that TBP, IPO8 and PDHB were suitable reference genes in cluster headache fibroblasts. This finding is the first report of an association between a variant in a gene encoding an ion-channel and cluster headache, and the first significant genetic evidence of calcium involvement in cluster headache pathophysiology.
Highlights
Cluster headache (CH) is a trigeminal autonomic cephalalgia; patients typically suffer from recurrent unilateral headaches of extremely severe pain, accompanied by unilateral autonomic symptoms and restlessness [1]
586 control subjects and 628 individuals with CH from a Swedish biobank were genotyped for four different markers (Table 2) which are suggested to be linked to response to verapamil in migraine
A secondary analysis under a dominant model confirmed the trend for a protective association between rs2230433 and CH; odds ratio (OR) 0.79, 95% confidence interval (CI) 0.63–0.99, p = 0.043
Summary
Cluster headache (CH) is a trigeminal autonomic cephalalgia; patients typically suffer from recurrent unilateral headaches of extremely severe pain, accompanied by unilateral autonomic symptoms and restlessness [1]. Around 15% of the patients are classified as chronic and have no, or very short, remission periods [1]. Another striking singularity of CH is that two thirds of the patients report that their attacks appear with a circadian pattern [3,4]. There is evidence of activation of the trigeminal nerve by calcitonin gene-related peptide (CGRP) release [6,7]. This probably entrains the activation of the trigeminal autonomic reflex responsible for the autonomic symptoms experienced during an attack [1]. The hypothalamus is reported to be activated during a CH attack, a possible
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