Abstract
Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase (NOS) genes, inducible NOS (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS), and tested for association with cluster headache. Swedish cluster headache patients (n = 542) and controls (n = 581) were genotyped using TaqMan® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 (p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use (p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.
Highlights
Nitric oxide (NO) is a vasodilating molecule and neurotransmitter frequently discussed as a player involved in the pathophysiology of cluster headache (CH)
Statistic tests confirmed a weak association between this single nucleotide polymorphisms (SNPs) and CH, which did not remain after correction for multiple testing
Allele frequencies in endothelial NOS (eNOS) and neuronal NOS (nNOS) variants as well as rs2297518 in inducible NOS (iNOS) were distributed in CH patients and controls
Summary
Nitric oxide (NO) is a vasodilating molecule and neurotransmitter frequently discussed as a player involved in the pathophysiology of cluster headache (CH). CH is classified as a trigeminal autonomic cephalalgia, the pathology characterized by excruciatingly painful attacks located around the eye. In active periods, these attacks occur at a frequency of one attack every other day to up to eight attacks per day. During CH attacks there is an activation of the autonomic-trigeminal reflex, where calcitonin gene-related peptide (CGRP) is released from trigeminal neurons innervating the dura mater, resulting in local inflammation and pain [3,4]. NO is involved in many of the biological processes that drive CH attacks, e.g., vasodilation, inflammation and pain signaling [5,6], and signs of elevated levels of NO activity have been detected in patients [7]. Changes in NO levels or related molecules could have an impact on CH pathophysiology
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